1
|
Zhang J, Ju T, Qin Y, Hou M, Gao L, Wu LA. Therapeutic targeting of P2X receptors for orofacial pain. Brain Res Bull 2025; 224:111301. [PMID: 40086763 DOI: 10.1016/j.brainresbull.2025.111301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/16/2025] [Accepted: 03/10/2025] [Indexed: 03/16/2025]
Abstract
P2X receptors (P2XRs), membrane ion channels activated by extracellular adenosine 5' -triphosphate (ATP), play a pivotal role in nociception by directly promoting pain signaling. Currently, antagonists targeting P2XRs have taken effect in alleviating various pain. The therapeutic potential of the P2X receptor family has become a central focus. Consequently, numerous research groups and pharmaceutical companies are actively engaged in developing novel P2XR antagonists. Furthermore, an increasing number of clinical trials on P2XR antagonists have obtained encouraging results. This review provides an overview of the structural characteristics and cellular localization of P2XRs, their molecular mechanisms and signaling pathways implicated in orofacial pain. Additionally, it explores the development of P2XR antagonists and their therapeutic application for managing orofacial pain. In conclusion, this review highlights the promising role of P2XRs as therapeutic targets for orofacial pain treatment.
Collapse
Affiliation(s)
- Jing Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Pediatric Den-tistry, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
| | - Tianjuan Ju
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Pediatric Den-tistry, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
| | - Yaru Qin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Pediatric Den-tistry, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
| | - Ming Hou
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Pediatric Den-tistry, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
| | - Lei Gao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Pediatric Den-tistry, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
| | - Li-An Wu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Pediatric Den-tistry, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
| |
Collapse
|
2
|
Ermakova E, Svitko S, Kabirova A, Nevsky E, Yakovleva O, Gilizhdinova K, Shaidullova K, Hermann A, Sitdikova G. The Role of Purinergic Mechanisms in the Excitability of Trigeminal Afferents of Rats with Prenatal Hyperhomocysteinemia. Biomolecules 2025; 15:419. [PMID: 40149955 PMCID: PMC11940108 DOI: 10.3390/biom15030419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 03/11/2025] [Accepted: 03/13/2025] [Indexed: 03/29/2025] Open
Abstract
Elevated levels of homocysteine in the blood plasma (hyperhomocysteinemia, HHCY) positively correlate with migraine symptoms in patients. Experimental studies show a higher sensitivity of rats with prenatal HHCY (pHHCY) to migraine symptoms like allodynia, photophobia, anxiety, and a higher excitability of meningeal trigeminal afferents. In the present study, the roles of purinergic mechanisms in the homocysteine-induced hyperexcitability of the trigeminal ganglion (TG) system using electrophysiological recordings from the trigeminal nerve, Ca2+ imaging of cells isolated from TG, and mast cell staining in meninges were investigated. Experiments were performed using rats with pHHCY born from females fed with a high-methionine-containing diet before and during pregnancy. Firstly, we found that lower concentrations of 4-aminopyridine, a K+-channel blocker, were able to induce an increase in the nociceptive activity of trigeminal afferents, supporting the hypothesis of the higher excitability of the trigeminal nerve of rats with pHHCY. Trigeminal afferents of rats with pHHCY were more sensitive to the exogenous application of the nonspecific agonist of purinergic ATP receptors. In neurons and satellite glial cells of TG of rats with pHHCY ATP, ADP (an agonist of metabotropic P2Y receptors) and BzATP (an agonist of ionotropic P2X with especially high potency for the P2X7 receptor) induced larger Ca2+ transients. The incubation of TG neurons in homocysteine for 24 h increased the ratio of neurons responding simultaneously to ATP and capsaicin. Moreover, rats with pHHCY exhibit a higher rate of degranulation of mast cells and increased response to the agonist of the P2X7 receptor BzATP application. In addition, higher levels of calcitonin gene-related peptide (CGRP) were found in rats with pHHCY. Our results suggest that chronic elevated levels of homocysteine induce the upregulation of ionotropic or metabotropic ATP receptors in neurons, satellite glial cells, and mast cells, which further provide inflammatory conditions and the sensitization of peripheral afferents underlying pain.
Collapse
Affiliation(s)
- Elizaveta Ermakova
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia; (E.E.); (S.S.); (A.K.); (E.N.); (O.Y.); (K.G.); (K.S.)
| | - Svetlana Svitko
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia; (E.E.); (S.S.); (A.K.); (E.N.); (O.Y.); (K.G.); (K.S.)
| | - Alsu Kabirova
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia; (E.E.); (S.S.); (A.K.); (E.N.); (O.Y.); (K.G.); (K.S.)
| | - Egor Nevsky
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia; (E.E.); (S.S.); (A.K.); (E.N.); (O.Y.); (K.G.); (K.S.)
| | - Olga Yakovleva
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia; (E.E.); (S.S.); (A.K.); (E.N.); (O.Y.); (K.G.); (K.S.)
| | - Karina Gilizhdinova
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia; (E.E.); (S.S.); (A.K.); (E.N.); (O.Y.); (K.G.); (K.S.)
| | - Kseniia Shaidullova
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia; (E.E.); (S.S.); (A.K.); (E.N.); (O.Y.); (K.G.); (K.S.)
| | - Anton Hermann
- Department of Biosciences, University of Salzburg, Hellbrunnerstr. 34, 5020 Salzburg, Austria;
| | - Guzel Sitdikova
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., 420008 Kazan, Russia; (E.E.); (S.S.); (A.K.); (E.N.); (O.Y.); (K.G.); (K.S.)
| |
Collapse
|
3
|
Ten Barge JA, van den Bosch GE, Slater R, van den Hoogen NJ, Reiss IKM, Simons SHP. Visceral Pain in Preterm Infants with Necrotizing Enterocolitis: Underlying Mechanisms and Implications for Treatment. Paediatr Drugs 2025; 27:201-220. [PMID: 39752054 PMCID: PMC11829917 DOI: 10.1007/s40272-024-00676-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/03/2024] [Indexed: 01/04/2025]
Abstract
Necrotizing enterocolitis (NEC) is a relatively rare but very severe gastrointestinal disease primarily affecting very preterm infants. NEC is characterized by excessive inflammation and ischemia in the intestines, and is associated with prolonged, severe visceral pain. Despite its recognition as a highly painful disease, current pain management for NEC is often inadequate, and research on optimal analgesic therapy for these patients is lacking. Insight into the mechanisms underlying intestinal pain in infants with NEC-visceral pain-could help identify the most effective analgesics for these vulnerable patients. Therefore, this comprehensive review aims to provide an overview of visceral nociception, including transduction, transmission, modulation, and experience, and discuss the implications for analgesic therapy in preterm infants with NEC. The transmission of visceral pain differs from that of somatic pain, contributing to the diffuse nature of visceral pain. Studies evaluating the effectiveness of analgesics for treating visceral pain in infants are scarce. However, research in visceral pain models highlights agents that may be particularly effective for treating visceral pain based on their mechanisms of action. Further research is necessary to determine whether agents that have shown promise for treating visceral pain in preclinical studies and adults are effective in infants with NEC as well.
Collapse
Affiliation(s)
- Judith A Ten Barge
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands.
| | - Gerbrich E van den Bosch
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands
| | | | | | - Irwin K M Reiss
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Sinno H P Simons
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands
| |
Collapse
|
4
|
Luo Z, Zhang Z, Li P, Yi M, Luo A, Zeng H, Wang T, Wang J, Nie H. The analgesic effect and mechanism of the active components screening from Corydalis yanhusuo by P2X3 receptors. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118989. [PMID: 39461390 DOI: 10.1016/j.jep.2024.118989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 10/17/2024] [Accepted: 10/23/2024] [Indexed: 10/29/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cavidine (CAV) is the main bioactive ingredient of Corydalis ternata f. yanhusuo (Y.H.Chou & Chun C.Hsu) Y.C.Zhu, which is a traditional Chinese herbal containing a variety of uses such as analgesic, anticancer, and anti-inflammatory properties. AIM OF THE STUDY The goal is to screen Corydalis yanhusuo for anti-central sensitization active components and investigate and clarify the pharmacological mechanism and therapeutic efficacy of the active ingredient CAV in the treatment of chronic pain. MATERIAL AND METHODS First, cell membrane immobilized chromatography was used to screen the bioactive ingredients in Corydalis yanhusuo. Spare nerve injury (SNI) model and complete Freund's adjuvant (CFA) mice model were constructed to identify the analgesic effect of CAV. RNA-seq and bioinformatics analyses were used to explore the potential targets of CAV in CFA mice and SNI mice. HE staining was used to observe the infiltration of inflammatory cells in the dorsal root ganglion (DRG) and spinal cord(SC) of CFA mice and SNI mice. WB and qPCR were used to detect the level of inflammatory factors TNF-α, IL-1β, and IL-6 in DRG and SC of mice. SNI and CFA mice were used to study the effect and mechanism of CAV on microglial activation. RESULTS 9 potential active ingredients were screened out from Corydalis yanhusuo that can regulate P2X3 receptors. CAV showed good analgesic effects, increased the mechanical pain and thermal pain thresholds of CFA mice and SNI mice, inhibited the expression of DRG and SC inflammatory factors, downregulated IBA-1, and inhibited microglial activation. Further in vivo and in vitro experiments showed that CAV significantly inhibited the expression of P2X3 receptors and the activation of its downstream MAPK pathway in DRG neurons and SC. CONCLUSION This study is the first to indicate that CAV exerts an analgesic effect by inhibiting microglia activation via the P2X3 signaling pathway axis, providing the clinical utility of CAV in chronic pain therapy.
Collapse
Affiliation(s)
- Zhenhui Luo
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Zhenglang Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Peiyang Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Mengqin Yi
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Anqi Luo
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Hekun Zeng
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Tingting Wang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Junlin Wang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Hong Nie
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
| |
Collapse
|
5
|
Sapio MR, King DM, Staedtler ES, Maric D, Jahanipour J, Kurochkina NA, Manalo AP, Ghetti A, Mannes AJ, Iadarola MJ. Expression pattern analysis and characterization of the hereditary sensory and autonomic neuropathy 2 A (HSAN2A) gene with no lysine kinase (WNK1) in human dorsal root ganglion. Exp Neurol 2023; 370:114552. [PMID: 37793538 DOI: 10.1016/j.expneurol.2023.114552] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/20/2023] [Accepted: 09/27/2023] [Indexed: 10/06/2023]
Abstract
Inherited painless neuropathies arise due to genetic insults that either block the normal signaling of or destroy the sensory afferent neurons in the dorsal root ganglion (DRG) responsible for transducing noxious stimuli. Complete loss of these neurons leads to profound insensitivity to all sensory modalities including pain. Hereditary sensory and autonomic neuropathy type 2 (HSNAII) is a rare genetic neuropathy characterized by a progressive distal early onset sensory loss. This syndrome is caused by autosomal recessive mutations in the with-no-lysine protein kinase 1 (WNK1) serine-threonine kinase gene. Of interest, disease-associated mutations are found in the large exon, termed "HSN2," which encodes a 498 amino acid domain C-terminal to the kinase domain. These mutations lead to truncation of the HSN2-containing proteins through the addition of an early stop codon (nonsense mutation) leading to loss of the C-terminal domains of this large protein. The present study evaluates the transcripts, gene structure, and protein structure of HSN2-containing WNK1 splice variants in DRG and spinal cord in order to establish the basal expression patterns of WNK1 and HSN2-containing WNK1 splice variants using multiplex fluorescent situ hybridization. We hypothesized that these transcripts would be enriched in pain-sensing DRG neurons, and, potentially, that enrichment in nociceptive neurons was responsible for the painless phenotypes observed. However, our in-depth analyses revealed that the HSN2-WNK1 splice variants were ubiquitously expressed but were not enriched in tachykinin 1-expressing C-fiber neurons, a class of neurons with a highly nociceptive character. We subsequently identified other subpopulations of DRG neurons with higher levels of HSN2-WNK1 expression, including mechanosensory large fibers. These data are inconsistent with the hypothesis that this transcript is enriched in nociceptive fibers, and instead suggest it may be related to general axon maintenance, or that nociceptive fibers are more sensitive to the genetic insult. These findings clarify the molecular and cellular expression pattern of this painless neuropathy gene in human tissue.
Collapse
Affiliation(s)
- Matthew R Sapio
- Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Diana M King
- Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ellen S Staedtler
- Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Dragan Maric
- National Institute of Neurological Disorders and Stroke, Flow and Imaging Cytometry Core Facility, Bethesda, MD 20892, USA
| | - Jahandar Jahanipour
- National Institute of Neurological Disorders and Stroke, Flow and Imaging Cytometry Core Facility, Bethesda, MD 20892, USA
| | | | - Allison P Manalo
- Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | | | - Andrew J Mannes
- Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Michael J Iadarola
- Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
| |
Collapse
|
6
|
Elati K, Tajeri S, Obara I, Mhadhbi M, Zweygarth E, Darghouth MA, Nijhof AM. Dual RNA-seq to catalogue host and parasite gene expression changes associated with virulence of T. annulata-transformed bovine leukocytes: towards identification of attenuation biomarkers. Sci Rep 2023; 13:18202. [PMID: 37875584 PMCID: PMC10598219 DOI: 10.1038/s41598-023-45458-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 10/19/2023] [Indexed: 10/26/2023] Open
Abstract
The apicomplexan parasite Theileria annulata is transmitted by Hyalomma ticks and causes an acute lymphoproliferative disease that is invariably lethal in exotic cattle breeds. The unique ability of the schizont stage of T. annulata to transform infected leukocytes to a cancer-like phenotype and the simplicity of culturing and passaging T. annulata-transformed cells in vitro have been explored for live vaccine development by attenuating the transformed cells using lengthy serial propagation in vitro. The empirical in vivo evaluation of attenuation required for each batch of long-term cultured cells is a major constraint since it is resource intensive and raises ethical issues regarding animal welfare. As yet, the molecular mechanisms underlying attenuation are not well understood. Characteristic changes in gene expression brought about by attenuation are likely to aid in the identification of novel biomarkers for attenuation. We set out to undertake a comparative transcriptome analysis of attenuated (passage 296) and virulent (passage 26) bovine leukocytes infected with a Tunisian strain of T. annulata termed Beja. RNA-seq was used to analyse gene expression profiles and the relative expression levels of selected genes were verified by real-time quantitative PCR (RT-qPCR) analysis. Among the 3538 T. annulata genes analysed, 214 were significantly differentially expressed, of which 149 genes were up-regulated and 65 down-regulated. Functional annotation of differentially expressed T. annulata genes revealed four broad categories of metabolic pathways: carbon metabolism, oxidative phosphorylation, protein processing in the endoplasmic reticulum and biosynthesis of secondary metabolites. It is interesting to note that of the top 40 genes that showed altered expression, 13 were predicted to contain a signal peptide and/or at least one transmembrane domain, suggesting possible involvement in host-parasite interaction. Of the 16,514 bovine transcripts, 284 and 277 showed up-regulated and down-regulated expression, respectively. These were assigned to functional categories relevant to cell surface, tissue morphogenesis and regulation of cell adhesion, regulation of leucocyte, lymphocyte and cell activation. The genetic alterations acquired during attenuation that we have catalogued herein, as well as the accompanying in silico functional characterization, do not only improve understanding of the attenuation process, but can also be exploited by studies aimed at identifying attenuation biomarkers across different cell lines focusing on some host and parasite genes that have been highlighted in this study, such as bovine genes (CD69, ZNF618, LPAR3, and APOL3) and parasite genes such as TA03875.
Collapse
Affiliation(s)
- Khawla Elati
- Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Robert-Von-Ostertag-Str. 7, 14163, Berlin, Germany.
- Veterinary Centre for Resistance Research, Freie Universität Berlin, Robert-Von-Ostertag-Str. 8, 14163, Berlin, Germany.
- Laboratoire de Parasitologie, École Nationale de Médecine Vétérinaire de Sidi Thabet, Institution de la Recherche et de l'Enseignement Supérieur Agricoles, Univ. Manouba, 2020, Sidi Thabet, Tunisia.
| | - Shahin Tajeri
- Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Robert-Von-Ostertag-Str. 7, 14163, Berlin, Germany
- Veterinary Centre for Resistance Research, Freie Universität Berlin, Robert-Von-Ostertag-Str. 8, 14163, Berlin, Germany
| | - Isaiah Obara
- Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Robert-Von-Ostertag-Str. 7, 14163, Berlin, Germany
- Veterinary Centre for Resistance Research, Freie Universität Berlin, Robert-Von-Ostertag-Str. 8, 14163, Berlin, Germany
| | - Moez Mhadhbi
- Laboratoire de Parasitologie, École Nationale de Médecine Vétérinaire de Sidi Thabet, Institution de la Recherche et de l'Enseignement Supérieur Agricoles, Univ. Manouba, 2020, Sidi Thabet, Tunisia
| | - Erich Zweygarth
- Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Robert-Von-Ostertag-Str. 7, 14163, Berlin, Germany
- Department of Veterinary Tropical Diseases, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa
| | - Mohamed Aziz Darghouth
- Laboratoire de Parasitologie, École Nationale de Médecine Vétérinaire de Sidi Thabet, Institution de la Recherche et de l'Enseignement Supérieur Agricoles, Univ. Manouba, 2020, Sidi Thabet, Tunisia
| | - Ard Menzo Nijhof
- Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Robert-Von-Ostertag-Str. 7, 14163, Berlin, Germany.
- Veterinary Centre for Resistance Research, Freie Universität Berlin, Robert-Von-Ostertag-Str. 8, 14163, Berlin, Germany.
| |
Collapse
|
7
|
Samhan-Arias AK, Poejo J, Marques-da-Silva D, Martínez-Costa OH, Gutierrez-Merino C. Hexa-Histidine, a Peptide with Versatile Applications in the Study of Amyloid-β(1-42) Molecular Mechanisms of Action. Molecules 2023; 28:7138. [PMID: 38067638 PMCID: PMC10708093 DOI: 10.3390/molecules28237909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/10/2023] [Accepted: 10/13/2023] [Indexed: 12/18/2023] Open
Abstract
Amyloid β (Aβ) oligomers are the most neurotoxic forms of Aβ, and Aβ(1-42) is the prevalent Aβ peptide found in the amyloid plaques of Alzheimer's disease patients. Aβ(25-35) is the shortest peptide that retains the toxicity of Aβ(1-42). Aβ oligomers bind to calmodulin (CaM) and calbindin-D28k with dissociation constants in the nanomolar Aβ(1-42) concentration range. Aβ and histidine-rich proteins have a high affinity for transition metal ions Cu2+, Fe3+ and Zn2+. In this work, we show that the fluorescence of Aβ(1-42) HiLyteTM-Fluor555 can be used to monitor hexa-histidine peptide (His6) interaction with Aβ(1-42). The formation of His6/Aβ(1-42) complexes is also supported by docking results yielded by the MDockPeP Server. Also, we found that micromolar concentrations of His6 block the increase in the fluorescence of Aβ(1-42) HiLyteTM-Fluor555 produced by its interaction with the proteins CaM and calbindin-D28k. In addition, we found that the His6-tag provides a high-affinity site for the binding of Aβ(1-42) and Aβ(25-35) peptides to the human recombinant cytochrome b5 reductase, and sensitizes this enzyme to inhibition by these peptides. In conclusion, our results suggest that a His6-tag could provide a valuable new tool to experimentally direct the action of neurotoxic Aβ peptides toward selected cellular targets.
Collapse
Affiliation(s)
- Alejandro K. Samhan-Arias
- Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), C/Arturo Duperier 4, 28029 Madrid, Spain;
- Instituto de Investigaciones Biomédicas ‘Sols-Morreale’ (CSIC-UAM), C/Arturo Duperier 4, 28029 Madrid, Spain
| | - Joana Poejo
- Instituto de Biomarcadores de Patologías Moleculares, Universidad de Extremadura, 06006 Badajoz, Spain;
| | - Dorinda Marques-da-Silva
- LSRE—Laboratory of Separation and Reaction Engineering and LCM—Laboratory of Catalysis and Materials, School of Management and Technology, Polytechnic Institute of Leiria, Morro do Lena-Alto do Vieiro, 2411-901 Leiria, Portugal;
- ALiCE—Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal
- School of Technology and Management, Polytechnic Institute of Leiria, Morro do Lena-Alto do Vieiro, 2411-901 Leiria, Portugal
| | - Oscar H. Martínez-Costa
- Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), C/Arturo Duperier 4, 28029 Madrid, Spain;
- Instituto de Investigaciones Biomédicas ‘Sols-Morreale’ (CSIC-UAM), C/Arturo Duperier 4, 28029 Madrid, Spain
| | - Carlos Gutierrez-Merino
- Instituto de Biomarcadores de Patologías Moleculares, Universidad de Extremadura, 06006 Badajoz, Spain;
| |
Collapse
|
8
|
Giniatullin R, Nistri A. Role of ATP in migraine mechanisms: focus on P2X3 receptors. J Headache Pain 2023; 24:1. [PMID: 36597043 PMCID: PMC9809127 DOI: 10.1186/s10194-022-01535-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 12/16/2022] [Indexed: 01/04/2023] Open
Abstract
Migraine is a major health burden worldwide with complex pathophysiology and multifarious underlying mechanisms. One poorly understood issue concerns the early steps in the generation of migraine pain. To elucidate the basic process of migraine pain further, it seems useful to consider key molecular players that may operate synergistically to evoke headache. While the neuropeptide CGRP is an important contributor, we propose that extracellular ATP (that generally plays a powerful nociceptive role) is also a major component of migraine headache, acting in concert with CGRP to stimulate trigeminal nociceptive neurons. The aim of the present focused review is to highlight the role of ATP activating its P2X3 membrane receptors selectively expressed by sensory neurons including their nerve fiber terminals in the meninges. Specifically, we present data on the homeostasis of ATP and related purines in the trigeminovascular system and in the CNS; the basic properties of ATP signalling at peripheral and central nerve terminals; the characteristics of P2X3 and related receptors in trigeminal neurons; the critical speed and persistence of P2X3 receptor activity; their cohabitation at the so-called meningeal neuro-immune synapse; the identity of certain endogenous agents cooperating with ATP to induce neuronal sensitization in the trigeminal sensory system; the role of P2X3 receptors in familial type migraine; the current state of P2X3 receptor antagonists and their pharmacological perspectives in migraine. It is proposed that the unique kinetic properties of P2X3 receptors activated by ATP offer an interesting translational value to stimulate future studies for innovative treatments of migraine pain.
Collapse
Affiliation(s)
- R. Giniatullin
- grid.9668.10000 0001 0726 2490A.I Virtanen Institute, University of Eastern Finland, 70211 Kuopio, Finland
| | - A. Nistri
- grid.5970.b0000 0004 1762 9868Department of Neuroscience, International School for Advanced Studies (SISSA), 34136 Trieste, Italy
| |
Collapse
|
9
|
Ding X, Yu F, He X, Xu S, Yang G, Ren W. Rubbing Salt in the Wound: Molecular Evolutionary Analysis of Pain-Related Genes Reveals the Pain Adaptation of Cetaceans in Seawater. Animals (Basel) 2022; 12:3571. [PMID: 36552490 PMCID: PMC9774174 DOI: 10.3390/ani12243571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/26/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Pain, usually caused by a strong or disruptive stimulus, is an unpleasant sensation that serves as a warning to organisms. To adapt to extreme environments, some terrestrial animals have evolved to be inherently insensitive to pain. Cetaceans are known as supposedly indifferent to pain from soft tissue injury representatives of marine mammals. However, the molecular mechanisms that explain how cetaceans are adapted to pain in response to seawater environment remain unclear. Here, we performed a molecular evolutionary analysis of pain-related genes in selected representatives of cetaceans. ASIC4 gene was identified to be pseudogenized in all odontocetes (toothed whales) except from Physeter macrocephalus (sperm whales), and relaxed selection of this gene was detected in toothed whales with pseudogenized ASIC4. In addition, positive selection was detected in pain perception (i.e., ASIC3, ANO1, CCK, and SCN9A) and analgesia (i.e., ASIC3, ANO1, CCK, and SCN9A) genes among the examined cetaceans. In this study, potential convergent amino acid substitutions within predicted proteins were found among the examined cetaceans and other terrestrial mammals, inhabiting extreme environments (e.g., V441I of TRPV1 in cetaceans and naked mole rats). Moreover, specific amino acid substitutions within predicted sequences of several proteins were found in the studied representatives of cetaceans (e.g., F56L and D163A of ASIC3, E88G of GRK2, and F159L of OPRD1). Most of the substitutions were located within important functional domains of proteins, affecting their protein functions. The above evidence suggests that cetaceans might have undergone adaptive molecular evolution in pain-related genes through different evolutionary patterns to adapt to pain, resulting in greater sensitivity to pain and more effective analgesia. This study could have implications for diagnosis and treatment of human pain.
Collapse
Affiliation(s)
- Xiaoyue Ding
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210000, China
| | - Fangfang Yu
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210000, China
| | - Xiaofang He
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210000, China
| | - Shixia Xu
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210000, China
| | - Guang Yang
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210000, China
| | - Wenhua Ren
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210000, China
| |
Collapse
|
10
|
Yuan ZL, Liu XD, Zhang ZX, Li S, Tian Y, Xi K, Cai J, Yang XM, Liu M, Xing GG. Activation of GDNF-ERK-Runx1 signaling contributes to P2X3R gene transcription and bone cancer pain. iScience 2022; 25:104936. [PMID: 36072549 PMCID: PMC9441333 DOI: 10.1016/j.isci.2022.104936] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 07/15/2022] [Accepted: 08/10/2022] [Indexed: 11/24/2022] Open
Abstract
Bone cancer pain is a common symptom in cancer patients with bone metastases and its underlying mechanisms remain unknown. Here, we report that Runx1 directly upregulates the transcriptional activity of P2X3 receptor (P2X3R) gene promoter in PC12 cells. Knocking down Runx1 in dorsal root ganglion (DRG) neurons suppresses the functional upregulation of P2X3R, attenuates neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats, whereas overexpressing Runx1 promotes P2X3R gene transcription in DRG neurons, induces neuronal hyperexcitability and pain hypersensitivity in naïve rats. Activation of GDNF-GFRα1-Ret-ERK signaling is required for Runx1-mediated P2X3R gene transcription in DRG neurons, and contributes to neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats. These findings indicate that the Runx1-mediated P2X3R gene transcription resulted from activation of GDNF-GFRα1-Ret-ERK signaling contributes to the sensitization of DRG neurons and pathogenesis of bone cancer pain. Our findings identify a potentially targetable mechanism that may cause bone metastasis-associated pain in cancer patients.
Collapse
Affiliation(s)
- Zhu-Lin Yuan
- Neuroscience Research Institute, Peking University, Beijing 100191, China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- Key Laboratory for Neuroscience, Ministry of Education of China and National Health Commission of China, Beijing 100191, China
| | - Xiao-Dan Liu
- Neuroscience Research Institute, Peking University, Beijing 100191, China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- Key Laboratory for Neuroscience, Ministry of Education of China and National Health Commission of China, Beijing 100191, China
| | - Zi-Xian Zhang
- Neuroscience Research Institute, Peking University, Beijing 100191, China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- Key Laboratory for Neuroscience, Ministry of Education of China and National Health Commission of China, Beijing 100191, China
| | - Song Li
- Neuroscience Research Institute, Peking University, Beijing 100191, China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- Key Laboratory for Neuroscience, Ministry of Education of China and National Health Commission of China, Beijing 100191, China
| | - Yue Tian
- Neuroscience Research Institute, Peking University, Beijing 100191, China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- Key Laboratory for Neuroscience, Ministry of Education of China and National Health Commission of China, Beijing 100191, China
| | - Ke Xi
- Neuroscience Research Institute, Peking University, Beijing 100191, China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- Key Laboratory for Neuroscience, Ministry of Education of China and National Health Commission of China, Beijing 100191, China
| | - Jie Cai
- Neuroscience Research Institute, Peking University, Beijing 100191, China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- Key Laboratory for Neuroscience, Ministry of Education of China and National Health Commission of China, Beijing 100191, China
| | - Xiao-Mei Yang
- Department of Human Anatomy and Embryology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Min Liu
- Neuroscience Research Institute, Peking University, Beijing 100191, China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- Key Laboratory for Neuroscience, Ministry of Education of China and National Health Commission of China, Beijing 100191, China
| | - Guo-Gang Xing
- Neuroscience Research Institute, Peking University, Beijing 100191, China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- Key Laboratory for Neuroscience, Ministry of Education of China and National Health Commission of China, Beijing 100191, China
| |
Collapse
|
11
|
Valdez-Morales EE, Sánchez-Navarro CA, Reyes-Pavón D, Barrios-Garcia T, Ochoa-Cortes F, Barajas-Espinosa A, Barragán-Iglesias P, Guerrero-Alba R. TNF-α enhances sensory DRG neuron excitability through modulation of P2X3 receptors in an acute colitis model. Front Immunol 2022; 13:872760. [PMID: 36032155 PMCID: PMC9416886 DOI: 10.3389/fimmu.2022.872760] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 07/18/2022] [Indexed: 11/15/2022] Open
Abstract
Previous studies have demonstrated that acute colonic inflammation leads to an increase in dorsal root ganglia (DRG) neuronal excitability. However, the signaling elements implicated in this hyperexcitability have yet to be fully unraveled. Extracellular adenosine 5’-triphosphate (ATP) is a well-recognized sensory signaling molecule that enhances the nociceptive response after inflammation through activation of P2X3 receptors, which are expressed mainly by peripheral sensory neurons. The aim of this study is to continue investigating how P2X3 affects neuronal hypersensitivity in an acute colitis animal model. To achieve this, DNBS (Dinitrobenzene sulfonic acid; 200 mg/kg) was intrarectally administered to C57BL/6 mice, and inflammation severity was assessed according to the following parameters: weight loss, macroscopic and microscopic scores. Perforated patch clamp technique was used to evaluate neuronal excitability via measuring changes in rheobase and action potential firing in T8-L1 DRG neurons. A-317491, a well-established potent and selective P2X3 receptor antagonist, served to dissect their contribution to recorded responses. Protein expression of P2X3 receptors in DRG was evaluated by western blotting and immunofluorescence. Four days post-DNBS administration, colons were processed for histological analyses of ulceration, crypt morphology, goblet cell density, and immune cell infiltration. DRG neurons from DNBS-treated mice were significantly more excitable compared with controls; these changes correlated with increased P2X3 receptor expression. Furthermore, TNF-α mRNA expression was also significantly higher in inflamed colons compared to controls. Incubation of control DRG neurons with TNF-α resulted in similar cell hyperexcitability as measured in DNBS-derived neurons. The selective P2X3 receptor antagonist, A-317491, blocked the TNF-α-induced effect. These results support the hypothesis that TNF-α enhances colon-innervating DRG neuron excitability via modulation of P2X3 receptor activity.
Collapse
Affiliation(s)
| | - Carlos A. Sánchez-Navarro
- Departamento de Medicina, Centro de Ciencias de la Salud , Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Diana Reyes-Pavón
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Tonatiuh Barrios-Garcia
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Fernando Ochoa-Cortes
- Licenciatura en Enfermería, Escuela Superior de Huejutla, Universidad Autónoma del Estado de Hidalgo, Hidalgo, Mexico
| | - Alma Barajas-Espinosa
- Licenciatura en Enfermería, Escuela Superior de Huejutla, Universidad Autónoma del Estado de Hidalgo, Hidalgo, Mexico
| | - Paulino Barragán-Iglesias
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Raquel Guerrero-Alba
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
- *Correspondence: Raquel Guerrero-Alba,
| |
Collapse
|
12
|
An Q, Yue G, Yang X, Lou J, Shan W, Ding J, Jin Z, Hu Y, Du Q, Liao Q, Xie R, Xu J. Pathophysiological Role of Purinergic P2X Receptors in Digestive System Diseases. Front Physiol 2022; 12:781069. [PMID: 35002763 PMCID: PMC8740087 DOI: 10.3389/fphys.2021.781069] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/01/2021] [Indexed: 11/16/2022] Open
Abstract
P2X receptors (P2XRs) are trimeric, non-selective cation channels activated by extracellular ATP and widely distributed in the digestive system. P2XRs have an important role in the physiological function of the digestive system, such as neurotransmission, ion transports, proliferation and apoptosis, muscle contraction, and relaxation. P2XRs can be involved in pain mechanisms both centrally and in the periphery and confirmed the association of P2XRs with visceral pain. In the periphery, ATP can be released as a result of tissue injury, visceral distension, or sympathetic activation and can excite nociceptive primary afferents by acting at homomeric P2X(3)R or heteromeric P2X(2/3)R. Thus, peripheral P2XRs, and homomeric P2X(3) and/or heteromeric P2X(2/3)R in particular, constitute attractive targets for analgesic drugs. Recently studies have shown that P2XRs have made significant advances in inflammation and cancer. P2X7R mediates NLRP3 inflammasome activation, cytokine and chemokine release, T lymphocyte survival and differentiation, transcription factor activation, and cell death. The P2X7R is a potent stimulant of inflammation and immunity and a promoter of cancer cell growth. This makes P2X7R an appealing target for anti-inflammatory and anti-cancer therapy. It is believed that with the further study of P2XRs and its subtypes, P2XRs and its specific antagonists will be expected to be widely used in the treatment of human digestive diseases in the future.
Collapse
Affiliation(s)
- Qimin An
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Gengyu Yue
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Xiaoxu Yang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Jun Lou
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Weixi Shan
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Jianhong Ding
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Zhe Jin
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Yanxia Hu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Qian Du
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Qiushi Liao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Rui Xie
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Jingyu Xu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| |
Collapse
|
13
|
Seol SH, Chung G. Estrogen-dependent regulation of transient receptor potential vanilloid 1 (TRPV1) and P2X purinoceptor 3 (P2X3): Implication in burning mouth syndrome. J Dent Sci 2022; 17:8-13. [PMID: 35028015 PMCID: PMC8739235 DOI: 10.1016/j.jds.2021.06.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/14/2021] [Indexed: 12/20/2022] Open
Abstract
Sex differences in the nervous system have gained recent academic interest. While the prominent differences are observed in mood and anxiety disorders, growing number of evidences also suggest sex difference in pain perception. This review focuses on estrogen as the key molecule underlying such difference, because estrogen plays many functions in the nervous system, including modulation of transient receptor potential vanilloid 1 (TRPV1) and P2X purinoceptor 3 (P2X3), two important nociceptive receptors. Estrogen was shown in various studies to up-regulate TRPV1 expression through two distinct pathways, resulting in pro-nociceptive effect. However, estrogen alleviated pain in other studies, by down-regulating nerve growth factor (NGF)-activated pathways and TRPV1. Estrogen may also attenuate nociception by inhibiting P2X3 receptors and ATP-signaling. Understanding the mechanism underlying the pro- and anti-nociceptive effect of estrogen might be crucial to understand pathophysiology of the burning mouth syndrome (BMS), a common chronic orofacial pain disorder in menopausal women. The involvement of TRPV1 is strongly suspected because of burning sensation. Reduced estrogen level of the BMS patient might have caused increased activity of P2X3 receptors. Interestingly, the increased expression of TRPV1 and P2X3 in oral mucosa of BMS patients was reported. The combinational impact of differential modulation of TRPV1/P2X3 during menopause might be an important contributing factor of etiology of BMS. Understanding the estrogen-dependent regulation of nociceptive receptors may provide a valuable insight toward the peripheral mechanism of sex-difference in pain perception.
Collapse
Affiliation(s)
- Seon-Hong Seol
- College of Human Ecology, Seoul National University, Seoul, South Korea
| | - Gehoon Chung
- Department of Oral Physiology, School of Dentistry, Seoul National University, Seoul, South Korea
- Dental Research Institute, Seoul National University, Seoul, South Korea
| |
Collapse
|
14
|
Xia LP, Luo H, Ma Q, Xie YK, Li W, Hu H, Xu ZZ. GPR151 in nociceptors modulates neuropathic pain via regulating P2X3 function and microglial activation. Brain 2021; 144:3405-3420. [PMID: 34244727 DOI: 10.1093/brain/awab245] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 05/17/2021] [Accepted: 06/01/2021] [Indexed: 11/14/2022] Open
Abstract
Neuropathic pain is a major health problem that affects up to 7-10% of the population worldwide. Currently, neuropathic pain is difficult to treat due to its elusive mechanisms. Here we report that orphan G protein-coupled receptor 151 (GPR151) in nociceptive sensory neurons controls neuropathic pain induced by nerve injury. GPR151 was mainly expressed in nonpeptidergic C-fiber dorsal root ganglion (DRG) neurons and highly upregulated after nerve injury. Importantly, conditional knockout of Gpr151 in adult nociceptive sensory neurons significantly alleviated chronic constriction injury (CCI)-induced neuropathic pain-like behavior but did not affect basal nociception. Moreover, GPR151 in DRG neurons was required for CCI-induced neuronal hyperexcitability and upregulation of colony-stimulating factor 1 (CSF1), which is necessary for microglial activation in the spinal cord after nerve injury. Mechanistically, GPR151 coupled with P2X3 ion channels and promoted their functional activities in neuropathic pain-like hypersensitivity. Knockout of Gpr151 suppressed P2X3-mediated calcium elevation and spontaneous pain behavior in CCI mice. Conversely, overexpression of Gpr151 significantly enhanced P2X3-mediated calcium elevation and DRG neuronal excitability. Furthermore, knockdown of P2X3 in DRGs reversed CCI-induced CSF1 upregulation, spinal microglial activation, and neuropathic pain-like behavior. Finally, the co-expression of GPR151 and P2X3 was confirmed in small-diameter human DRG neurons, indicating the clinical relevance of our findings. Together, our results suggest that GPR151 in nociceptive DRG neurons plays a key role in the pathogenesis of neuropathic pain and could be a potential target for treating neuropathic pain.
Collapse
Affiliation(s)
- Li-Ping Xia
- Department of Neurobiology and Department of Anesthesiology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.,NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Hao Luo
- Department of Neurobiology and Department of Anesthesiology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.,NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Qiang Ma
- Department of Neurobiology and Department of Anesthesiology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.,NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Ya-Kai Xie
- Department of Neurobiology and Department of Anesthesiology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.,NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Wei Li
- Department of Neurobiology and Department of Anesthesiology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.,NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Hailan Hu
- Department of Neurobiology and Department of Anesthesiology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.,NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Zhen-Zhong Xu
- Department of Neurobiology and Department of Anesthesiology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.,NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
| |
Collapse
|
15
|
Li J, Zhang Y, Illes P, Tang Y, Rubini P. Increasing Efficiency of Repetitive Electroacupuncture on Purine- and Acid-Induced Pain During a Three-Week Treatment Schedule. Front Pharmacol 2021; 12:680198. [PMID: 34040538 PMCID: PMC8141797 DOI: 10.3389/fphar.2021.680198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 04/15/2021] [Indexed: 12/11/2022] Open
Abstract
Acupuncture (AP) is an important constituent of the therapeutic repertoire of traditional Chinese medicine and has been widely used to alleviate chronic painful conditions all over the world. We studied in rats the efficiency of electroacupuncture (EAP) applied to the Zusanli acupoint (ST36) as an analgesic treatment over a 3-week period of time on purine (α,β-methylene ATP, dibenzoyl-ATP)- and acid (pH 6.0 medium)-induced pain in the rat paw. The two ATP derivatives stimulated P2X3 and P2X7 receptors, respectively, while the slightly acidic medium stimulated the “acid-sensitive ion channel 3” (ASIC3). It was found that the P2X7 receptor and ASIC-mediated pain was counteracted by EAP with greater efficiency at the end than at the beginning of the treatment schedule, while the P2X3 receptor–mediated pain was not. Our findings have important clinical and theoretical consequences, among others, because they are difficult to reconcile with the assumption that AP is primarily due to the release of peripheral and central opioid peptides causing the well-known tolerance to their effects. In consequence, AP is a convenient therapeutic instrument to treat subacute and chronic pain.
Collapse
Affiliation(s)
- Jie Li
- School of Acupuncture and Tuina, Chengdu University of Traditional Medicine, Chengdu, China
| | - Ying Zhang
- School of Acupuncture and Tuina, Chengdu University of Traditional Medicine, Chengdu, China
| | - Peter Illes
- School of Acupuncture and Tuina, Chengdu University of Traditional Medicine, Chengdu, China.,International Collaborative Center on Big Science Plan for Purinergic Signalling, Chengdu University of Traditional Medicine, Chengdu, China.,Rudolf Boehm Institute for Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany
| | - Yong Tang
- School of Acupuncture and Tuina, Chengdu University of Traditional Medicine, Chengdu, China.,International Collaborative Center on Big Science Plan for Purinergic Signalling, Chengdu University of Traditional Medicine, Chengdu, China
| | - Patrizia Rubini
- School of Acupuncture and Tuina, Chengdu University of Traditional Medicine, Chengdu, China.,International Collaborative Center on Big Science Plan for Purinergic Signalling, Chengdu University of Traditional Medicine, Chengdu, China
| |
Collapse
|
16
|
Fan Y, Ji X, Zhang L, Zhang X. The Analgesic Effects of Static Magnetic Fields. Bioelectromagnetics 2021; 42:115-127. [PMID: 33508148 DOI: 10.1002/bem.22323] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 12/17/2020] [Accepted: 01/02/2021] [Indexed: 11/09/2022]
Abstract
Pain is one of the most common reasons why people seek medical care, which is related to most disease states. Magnetic fields (MFs) can be applied locally to specific parts of human bodies with high penetration and temporal control, which have a long-debated history in folk therapy. The purpose of this review is to collect and analyze experimental data about the analgesic effects of static magnetic fields (SMFs) so that we can have a scientific understanding regarding this topic. We collected 28 studies (25 English and 3 Chinese papers) with proper sham controls that investigated the effects of SMFs on pain relief in humans or mice. We found that 64% of the human studies and all mice studies in the literature showed positive analgesic effects of SMFs, which are related to factors including SMF intensity, treatment time, and pain types. Higher intensity and/or longer treatment time, as well as some specific pain types, may have better pain relief effects. Initial mechanistic studies indicated that membrane receptors, such as capsaicin receptor VR1/TRPV1, opioid receptors, and P2X3 receptors, might be involved. By describing experimental evidence and analysis, we found that SMFs actually hold considerable promise for managing some specific types of pain if proper SMF parameters are used. More studies comprehensively evaluating the parameters of SMF and its corresponding analgesic effects on different pain types, as well as the underlying molecular mechanisms, will be necessary to further validate its therapeutic potential in pain management in the future. Bioelectromagnetics. 00:00-00, 2021. © 2021 Bioelectromagnetics Society.
Collapse
Affiliation(s)
- Yixiang Fan
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
- Science Island Branch of Graduate School, University of Science and Technology of China, Hefei, China
| | - Xinmiao Ji
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
| | - Lei Zhang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
| | - Xin Zhang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
- Science Island Branch of Graduate School, University of Science and Technology of China, Hefei, China
- Institutes of Physical Science and Information Technology, Anhui University, Hefei, China
- International Magnetobiology Frontier Research Center (iMFRC), Science Island, Hefei, China
| |
Collapse
|
17
|
Zhang WJ, Luo C, Pu FQ, Zhu JF, Zhu Z. The role and pharmacological characteristics of ATP-gated ionotropic receptor P2X in cancer pain. Pharmacol Res 2020; 161:105106. [DOI: 10.1016/j.phrs.2020.105106] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/21/2020] [Accepted: 07/24/2020] [Indexed: 02/07/2023]
|
18
|
Koroleva K, Ermakova E, Mustafina A, Giniatullina R, Giniatullin R, Sitdikova G. Protective Effects of Hydrogen Sulfide Against the ATP-Induced Meningeal Nociception. Front Cell Neurosci 2020; 14:266. [PMID: 32982692 PMCID: PMC7492747 DOI: 10.3389/fncel.2020.00266] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 07/29/2020] [Indexed: 11/26/2022] Open
Abstract
We previously showed that extracellular ATP and hydrogen sulfide (H2S), a recently discovered gasotransmitter, are both triggering the nociceptive firing in trigeminal nociceptors implicated in migraine pain. ATP contributes to meningeal nociception by activating the P2X3 subunit-containing receptors whereas H2S operates mainly via TRP receptors. However, H2S was also proposed as a neuroprotective and anti-nociceptive agent. This study aimed to test the effect of H2S on ATP-mediated nociceptive responses in rat meningeal afferents and trigeminal neurons and on ATP-induced degranulation of dural mast cells. Electrophysiological recording of trigeminal nerve activity in meninges was supplemented by patch-clamp and calcium imaging studies of isolated trigeminal neurons. The H2S donor NaHS induced a mild activation of afferents and fully suppressed the subsequent ATP-induced firing of meningeal trigeminal nerve fibers. This anti-nociceptive effect of H2S was specific as an even stronger effect of capsaicin did not abolish the action of ATP. In isolated trigeminal neurons, NaHS decreased the inward currents and calcium transients evoked by activation of ATP-gated P2X3 receptors. Moreover, NaHS prevented ATP-induced P2X7 receptor-mediated degranulation of meningeal mast cells which emerged as triggers of migraine pain. Finally, NaHS decreased the concentration of extracellular ATP in the meningeal preparation. Thus, H2S exerted the multiple protective actions against the nociceptive effects of ATP. These data highlight the novel pathways to reduce purinergic mechanisms of migraine with pharmacological donors or by stimulation production of endogenous H2S.
Collapse
Affiliation(s)
- Kseniia Koroleva
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.,A.I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Elizaveta Ermakova
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Alsu Mustafina
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Raisa Giniatullina
- A.I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Rashid Giniatullin
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.,A.I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Guzel Sitdikova
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| |
Collapse
|
19
|
Retrograde Labeling of Different Distribution Features of DRG P2X2 and P2X3 Receptors in a Neuropathic Pain Rat Model. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9861459. [PMID: 32775458 PMCID: PMC7396081 DOI: 10.1155/2020/9861459] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/03/2020] [Accepted: 07/08/2020] [Indexed: 12/25/2022]
Abstract
The distributions of P2X subtypes during peripheral neuropathic pain conditions and their differential roles are not fully understood. To explore these characteristics, the lumbosacral dorsal root ganglion (DRG) in the chronic constriction injury (CCI) sciatic nerve rat model was studied. Retrograde trace labeling combined with immunofluorescence technology was applied to analyze the distribution of neuropathic nociceptive P2X1-6 receptors. Our results suggest that Fluoro-Gold (FG) retrograde trace labeling is an efficient method for studying lumbosacral DRG neurons in the CCI rat model, especially when the DRG neurons are divided into small, medium, and large subgroups. We found that neuropathic nociceptive lumbosacral DRG neurons (i.e., FG-positive cells) were significantly increased in medium DRG neurons, while they declined in the large DRG neurons in the CCI group. P2X3 receptors were markedly upregulated in medium while P2X2 receptors were significantly decreased in small FG-positive DRG neurons. There were no significant changes in other P2X receptors (including P2X1, P2X4, P2X5, and P2X6). We anticipate that P2X receptors modulate nociceptive sensitivity primarily through P2X3 subtypes that are upregulated in medium neuropathic nociceptive DRG neurons and/or via the downregulation of P2X2 cells in neuropathic nociceptive small DRG neurons.
Collapse
|
20
|
Currò D, Navarra P, Samengo I, Martire M. P2X7 receptors exert a permissive effect on the activation of presynaptic AMPA receptors in rat trigeminal caudal nucleus glutamatergic nerve terminals. J Headache Pain 2020; 21:83. [PMID: 32615921 PMCID: PMC7330953 DOI: 10.1186/s10194-020-01153-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/29/2020] [Indexed: 12/12/2022] Open
Abstract
Background Purine receptors play roles in peripheral and central sensitization and are associated with migraine headache. We investigated the possibility that ATP plays a permissive role in the activation of AMPA receptors thus inducing Glu release from nerve terminals isolated from the rat trigeminal caudal nucleus (TCN). Methods Nerve endings isolated from the rat TCN were loaded with [3H]D-aspartic acid ([3H]D-ASP), layered into thermostated superfusion chambers, and perfused continuously with physiological medium, alone or with various test drugs. Radioactivity was measured to assess [3H]D-ASP release under different experimental conditions. Results Synaptosomal [3H]D-ASP spontaneous release was stimulated by ATP and to an even greater extent by the ATP analogue benzoylbenzoylATP (BzATP). The stimulation of [3H]D-ASP basal release by the purinergic agonists was prevented by the selective P2X7 receptor antagonist A438079. AMPA had no effect on basal [3H]D-ASP release, but the release observed when synaptosomes were exposed to AMPA plus a purinoceptor agonist exceeded that observed with ATP or BzATP alone. The selective AMPA receptor antagonist NBQX blocked this “excess” release. Co-exposure to AMPA and BzATP, each at a concentration with no release-stimulating effects, evoked a significant increase in [3H]D-ASP basal release, which was prevented by exposure to a selective AMPA antagonist. Conclusions P2X7 receptors expressed on glutamatergic nerve terminals in the rat TCN can mediate Glu release directly and indirectly by facilitating the activation of presynaptic AMPA receptors. The high level of glial ATP that occurs during chronic pain states can promote widespread release of Glu as well as can increase the function of AMPA receptors. In this manner, ATP contributes to the AMPA receptor activation involved in the onset and maintenance of the central sensitization associated with chronic pain.
Collapse
Affiliation(s)
- Diego Currò
- Institute of Pharmacology, School of Medicine, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Pierluigi Navarra
- Institute of Pharmacology, School of Medicine, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Irene Samengo
- Institute of Pharmacology, School of Medicine, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Maria Martire
- Institute of Pharmacology, School of Medicine, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy.
| |
Collapse
|
21
|
He JR, Yu SG, Tang Y, Illes P. Purinergic signaling as a basis of acupuncture-induced analgesia. Purinergic Signal 2020; 16:297-304. [PMID: 32577957 PMCID: PMC7524941 DOI: 10.1007/s11302-020-09708-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 06/02/2020] [Indexed: 12/11/2022] Open
Abstract
This review summarizes experimental evidence indicating that purinergic mechanisms are causally involved in acupuncture (AP)-induced analgesia. Electroacupuncture (EAP) and manual AP release at pain-relevant acupoints ATP which may activate purinergic P2X receptors (Rs) especially of the P2X3 type situated at local sensory nerve endings (peripheral terminals of dorsal root ganglion [DRG] neurons); the central processes of these neurons are thought to inhibit via collaterals of ascending dorsal horn spinal cord neurons, pain-relevant pathways projecting to higher centers of the brain. In addition, during AP/EAP non-neuronal P2X4 and/or P2X7Rs localized at microglial cells of the CNS become activated at the spinal or supraspinal levels. In consequence, these microglia secrete bioactive compounds such as growth factors, cytokines, chemokines, reactive oxygen, and nitrogen species, which modulate the ascending neuronal pathways conducting painful stimuli. Alternatively, ATP released at acupoints by AP/EAP may be enzymatically degraded to adenosine, stimulating in loco presynaptic A1Rs exerting an inhibitory influence on the primary afferent fibers (the above mentioned pain-sensing peripheral terminals of DRG neurons) which thereby fail to conduct action potentials to the spinal cord dorsal horn. The net effect of the stimulation of P2X3, P2X4, P2X7, and A1Rs by the AP/EAP-induced release of ATP/adenosine at certain acupoints will be analgesia.
Collapse
Affiliation(s)
- Jin-Rong He
- International Collaborative Centre on Big Science Plan for Purine Signalling, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Shu-Guang Yu
- International Collaborative Centre on Big Science Plan for Purine Signalling, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.,Acupuncture & Chronobiology Key Laboratory of Sichuan Province, Chengdu, 610075, China
| | - Yong Tang
- International Collaborative Centre on Big Science Plan for Purine Signalling, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.,Acupuncture & Chronobiology Key Laboratory of Sichuan Province, Chengdu, 610075, China
| | - Peter Illes
- International Collaborative Centre on Big Science Plan for Purine Signalling, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China. .,Rudolf Boehm Institute for Pharmacology and Toxicology, University of Leipzig, 04107, Leipzig, Germany.
| |
Collapse
|
22
|
Dal Ben D, Antonioli L, Lambertucci C, Spinaci A, Fornai M, D'Antongiovanni V, Pellegrini C, Blandizzi C, Volpini R. Approaches for designing and discovering purinergic drugs for gastrointestinal diseases. Expert Opin Drug Discov 2020; 15:687-703. [PMID: 32228110 DOI: 10.1080/17460441.2020.1743673] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Purines finely modulate physiological motor, secretory, and sensory functions in the gastrointestinal tract. Their activity is mediated by the purinergic signaling machinery, including receptors and enzymes regulating their synthesis, release, and degradation. Several gastrointestinal dysfunctions are characterized by alterations affecting the purinergic system. AREAS COVERED The authors provide an overview on the purinergic receptor signaling machinery, the molecules and proteins involved, and a summary of medicinal chemistry efforts aimed at developing novel compounds able to modulate the activity of each player involved in this machinery. The involvement of purinergic signaling in gastrointestinal motor, secretory, and sensory functions and dysfunctions, and the potential therapeutic applications of purinergic signaling modulators, are then described. EXPERT OPINION A number of preclinical and clinical studies demonstrate that the pharmacological manipulation of purinergic signaling represents a viable way to counteract several gastrointestinal diseases. At present, the paucity of purinergic therapies is related to the lack of receptor-subtype-specific agonists and antagonists that are effective in vivo. In this regard, the development of novel therapeutic strategies should be focused to include tools able to control the P1 and P2 receptor expression as well as modulators of the breakdown or transport of purines.
Collapse
Affiliation(s)
- Diego Dal Ben
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Camerino, Italy
| | - Luca Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa , Pisa, Italy
| | - Catia Lambertucci
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Camerino, Italy
| | - Andrea Spinaci
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Camerino, Italy
| | - Matteo Fornai
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa , Pisa, Italy
| | - Vanessa D'Antongiovanni
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa , Pisa, Italy
| | | | - Corrado Blandizzi
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa , Pisa, Italy
| | - Rosaria Volpini
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Camerino, Italy
| |
Collapse
|
23
|
Zhang Y, Huang L, Kozlov SA, Rubini P, Tang Y, Illes P. Acupuncture alleviates acid- and purine-induced pain in rodents. Br J Pharmacol 2019; 177:77-92. [PMID: 31444978 DOI: 10.1111/bph.14847] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 08/12/2019] [Accepted: 08/14/2019] [Indexed: 12/14/2022] Open
Affiliation(s)
- Ying Zhang
- Acupuncture and Tuina School, Chengdu University of TCM, Chengdu, China
| | - Lumei Huang
- Acupuncture and Tuina School, Chengdu University of TCM, Chengdu, China
| | - Sergey A Kozlov
- Shemyakin-Ovchinikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - Patrizia Rubini
- Acupuncture and Tuina School, Chengdu University of TCM, Chengdu, China
| | - Yong Tang
- Acupuncture and Tuina School, Chengdu University of TCM, Chengdu, China
| | - Peter Illes
- Acupuncture and Tuina School, Chengdu University of TCM, Chengdu, China.,Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Universität Leipzig, Leipzig, Germany
| |
Collapse
|
24
|
The expression of purinergic P2X4 and P2X7 receptors in selected mesolimbic structures during morphine withdrawal in rats. Brain Res 2019; 1719:49-56. [PMID: 31121160 DOI: 10.1016/j.brainres.2019.05.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 05/14/2019] [Accepted: 05/19/2019] [Indexed: 12/19/2022]
Abstract
Morphine is one of the most potent analgesics used in medicine and it's long-term use is associated with the risk of the state of dependence. The cessation of chronic morphine administration leads to withdrawal signs which are associated with neurotransmitter dysregulations within mesolimbic system. Adenosine 5'-triphosphate (ATP) and purinergic system play an important role in the activity of central nervous system (CNS). Purinergic receptors are widely distributed in neurons and glial cells throughout the CNS taking part in integration of functional activity between neurons, glial and vascular cells. In the present study the mRNA and protein expression of purinergic P2X4 and P2X7 receptors in selected mesolimbic structures (striatum, hippocampus and prefrontal cortex) during morphine withdrawal in rats was investigated by RT-PCR and Western Blot analysis. Two experimental models of morphine withdrawal were studied: single and repeated morphine withdrawal. We demonstrated that expression of P2X4 and P2X7 receptors was altered during morphine withdrawal period in rats. These alterations were varied in particular mesolimbic areas depending on the scheme of morphine administration. Our results extend the current knowledge on morphine withdrawal and for the first time high-light interactions between purinergic system and morphine withdrawal. It seems, the purinergic system may be a new, valuable tool in searching for a new strategy of management of opioid dependence.
Collapse
|
25
|
Tang S, Zhou J, Jing H, Liao M, Lin S, Huang Z, Huang T, Zhong J, HanbingWang. Functional roles of lncRNAs and its potential mechanisms in neuropathic pain. Clin Epigenetics 2019; 11:78. [PMID: 31092294 PMCID: PMC6521530 DOI: 10.1186/s13148-019-0671-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 04/25/2019] [Indexed: 12/20/2022] Open
Abstract
Neuropathic pain (NP) is ranked as one of the major forms of chronic pain and emerges as a direct consequence of a lesion or disease affecting the somatosensory nervous system. Despite great advances into the mechanisms of NP, clinical practice is still not satisfactory. Fortunately, progress in elucidating unique features and multiple molecular mechanisms of long non-coding RNAs (lncRNAs) in NP has emerged in the past 10 years, suggesting that novel therapeutic strategies for pain treatment may be proposed. In this review, we will concentrate on recent studies associated with lncRNAs in NP. First, we will describe the alterations of lncRNA expression after spinal cord injury (SCI) and peripheral nerve injury (PNI), and then we illustrate the role of some specific lncRNAs in detail, which may offer new insights into our understanding of the etiology and pathophysiology of NP. Finally, we put special emphasis on the altered expression of lncRNAs in the diverse biological process of NP. Recent advances we summarized above in the development of NP may facilitate translation of these findings from bench to bedside in the future.
Collapse
Affiliation(s)
- Simin Tang
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, Guangdong Province, China.,Sun Yet-sen University, Guangzhou, 510000, Guangdong Province, China
| | - Jun Zhou
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, Guangdong Province, China.
| | - Huan Jing
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, Guangdong Province, China.,ZunYi Medical University, ZunYi, 563100, China
| | - Meijuan Liao
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, Guangdong Province, China
| | - Sen Lin
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, Guangdong Province, China
| | - Zhenxing Huang
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, Guangdong Province, China
| | - Teng Huang
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, Guangdong Province, China
| | - Jiying Zhong
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, Guangdong Province, China
| | - HanbingWang
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, Guangdong Province, China
| |
Collapse
|
26
|
Hossain MZ, Bakri MM, Yahya F, Ando H, Unno S, Kitagawa J. The Role of Transient Receptor Potential (TRP) Channels in the Transduction of Dental Pain. Int J Mol Sci 2019; 20:ijms20030526. [PMID: 30691193 PMCID: PMC6387147 DOI: 10.3390/ijms20030526] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 01/18/2019] [Accepted: 01/24/2019] [Indexed: 12/18/2022] Open
Abstract
Dental pain is a common health problem that negatively impacts the activities of daily living. Dentine hypersensitivity and pulpitis-associated pain are among the most common types of dental pain. Patients with these conditions feel pain upon exposure of the affected tooth to various external stimuli. However, the molecular mechanisms underlying dental pain, especially the transduction of external stimuli to electrical signals in the nerve, remain unclear. Numerous ion channels and receptors localized in the dental primary afferent neurons (DPAs) and odontoblasts have been implicated in the transduction of dental pain, and functional expression of various polymodal transient receptor potential (TRP) channels has been detected in DPAs and odontoblasts. External stimuli-induced dentinal tubular fluid movement can activate TRP channels on DPAs and odontoblasts. The odontoblasts can in turn activate the DPAs by paracrine signaling through ATP and glutamate release. In pulpitis, inflammatory mediators may sensitize the DPAs. They could also induce post-translational modifications of TRP channels, increase trafficking of these channels to nerve terminals, and increase the sensitivity of these channels to stimuli. Additionally, in caries-induced pulpitis, bacterial products can directly activate TRP channels on DPAs. In this review, we provide an overview of the TRP channels expressed in the various tooth structures, and we discuss their involvement in the development of dental pain.
Collapse
Affiliation(s)
- Mohammad Zakir Hossain
- Department of Oral Physiology, School of Dentistry, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan.
| | - Marina Mohd Bakri
- Department of Oral and Craniofacial Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur 50603, Malaysia.
| | - Farhana Yahya
- Department of Oral and Craniofacial Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur 50603, Malaysia.
| | - Hiroshi Ando
- Department of Biology, School of Dentistry, Matsumoto Dental University, 1780 Gobara, Hirooka, Shiojiri, Nagano 399-0781, Japan.
| | - Shumpei Unno
- Department of Oral Physiology, School of Dentistry, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan.
| | - Junichi Kitagawa
- Department of Oral Physiology, School of Dentistry, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan.
| |
Collapse
|
27
|
Arribas-Blázquez M, Olivos-Oré LA, Barahona MV, Sánchez de la Muela M, Solar V, Jiménez E, Gualix J, McIntosh JM, Ferrer-Montiel A, Miras-Portugal MT, Artalejo AR. Overexpression of P2X3 and P2X7 Receptors and TRPV1 Channels in Adrenomedullary Chromaffin Cells in a Rat Model of Neuropathic Pain. Int J Mol Sci 2019; 20:ijms20010155. [PMID: 30609840 PMCID: PMC6337219 DOI: 10.3390/ijms20010155] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 12/25/2018] [Accepted: 12/26/2018] [Indexed: 11/16/2022] Open
Abstract
We have tested the hypothesis that neuropathic pain acting as a stressor drives functional plasticity in the sympathoadrenal system. The relation between neuropathic pain and adrenal medulla function was studied with behavioral, immunohistochemical and electrophysiological techniques in rats subjected to chronic constriction injury of the sciatic nerve. In slices of the adrenal gland from neuropathic animals, we have evidenced increased cholinergic innervation and spontaneous synaptic activity at the splanchnic nerve–chromaffin cell junction. Likewise, adrenomedullary chromaffin cells displayed enlarged acetylcholine-evoked currents with greater sensitivity to α-conotoxin RgIA, a selective blocker of α9 subunit-containing nicotinic acetylcholine receptors, as well as increased exocytosis triggered by voltage-activated Ca2+ entry. Altogether, these adaptations are expected to facilitate catecholamine output into the bloodstream. Last, but most intriguing, functional and immunohistochemical data indicate that P2X3 and P2X7 purinergic receptors and transient receptor potential vanilloid-1 (TRPV1) channels are overexpressed in chromaffin cells from neuropathic animals. These latter observations are reminiscent of molecular changes characteristic of peripheral sensitization of nociceptors following the lesion of a peripheral nerve, and suggest that similar phenomena can occur in other tissues, potentially contributing to behavioral manifestations of neuropathic pain.
Collapse
Affiliation(s)
- Marina Arribas-Blázquez
- Department of Pharmacology and Toxicology, Veterinary Faculty, Universidad Complutense de Madrid, 28040 Madrid, Spain.
- Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, 28040 Madrid, Spain.
| | - Luis Alcides Olivos-Oré
- Department of Pharmacology and Toxicology, Veterinary Faculty, Universidad Complutense de Madrid, 28040 Madrid, Spain.
- Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, 28040 Madrid, Spain.
| | - María Victoria Barahona
- Department of Pharmacology and Toxicology, Veterinary Faculty, Universidad Complutense de Madrid, 28040 Madrid, Spain.
- Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, 28040 Madrid, Spain.
| | - Mercedes Sánchez de la Muela
- Department of Animal Medicine and Surgery, Veterinary Faculty, Universidad Complutense de Madrid, 28040 Madrid, Spain.
| | - Virginia Solar
- Department of Pharmacology and Toxicology, Veterinary Faculty, Universidad Complutense de Madrid, 28040 Madrid, Spain.
| | - Esperanza Jiménez
- Department of Pharmacology and Toxicology, Veterinary Faculty, Universidad Complutense de Madrid, 28040 Madrid, Spain.
| | - Javier Gualix
- Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, 28040 Madrid, Spain.
- Department of Biochemistry and Molecular Biology, Veterinary Faculty, Universidad Complutense de Madrid, 28040 Madrid, Spain.
| | - J Michael McIntosh
- George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT 84148, USA.
- Departments of Biology and Psychiatry, University of Utah, Salt Lake City, UT 84112, USA.
| | - Antonio Ferrer-Montiel
- Instituto de Biología Molecular y Celular (IBMC), Universitas Miguel Hernández, 03202 Elche, Spain.
| | - María Teresa Miras-Portugal
- Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, 28040 Madrid, Spain.
- Department of Biochemistry and Molecular Biology, Veterinary Faculty, Universidad Complutense de Madrid, 28040 Madrid, Spain.
| | - Antonio R Artalejo
- Department of Pharmacology and Toxicology, Veterinary Faculty, Universidad Complutense de Madrid, 28040 Madrid, Spain.
- Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, 28040 Madrid, Spain.
| |
Collapse
|
28
|
Liang Y, Gu Y, Shi R, Li G, Chen Y, Huang LYM. Electroacupuncture downregulates P2X3 receptor expression in dorsal root ganglia of the spinal nerve-ligated rat. Mol Pain 2019; 15:1744806919847810. [PMID: 30983496 PMCID: PMC6537063 DOI: 10.1177/1744806919847810] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 03/30/2019] [Accepted: 03/31/2019] [Indexed: 12/18/2022] Open
Abstract
Electroacupuncture has been shown to effectively reduce chronic pain in patients with nerve injury. The underlying mechanisms are not well understood. Accumulated evidence suggests that purinergic P2X3 receptors (P2X3Rs) in dorsal root ganglion neurons play a major role in mediating chronic pain associated with nerve injury. The aim of this study is to determine if electroacupuncture stimulation alters P2X3R activity in dorsal root ganglia to produce analgesia under neuropathic pain condition. Peripheral neuropathy was produced by ligation of the left lumbar 5 (L5) spinal nerve in rats. Low-frequency (2 Hz) electrical stimulation was applied to ipsilateral ST36 and BL60 acupoints in rats. The P2X3R agonist (α,β-meATP)-induced flinch responses were reduced after electroacupuncture treatment. Western analyses showed that P2X3R expression was upregulated in nerve-uninjured lumbar 4 (L4) dorsal root ganglion neurons ipsilateral to the spinal nerve ligation. Electroacupuncture-stimulation reversed the upregulation. In nerve-injured L5 dorsal root ganglia, P2X3R expression was substantially reduced. Electroacupuncture had no effect on the reduction. We also determined the injury state of P2X3R expressing dorsal root ganglion neurons using the neuronal injury marker, activating transcription factor 3 (ATF3). Immunohistochemical assay showed that in L4 dorsal root ganglia, almost all P2X3Rs were expressed in uninjured (ATF3-) neurons. Spinal nerve ligation increased the expression of P2X3Rs. Electroacupuncture reduced the increase in P2X3R expression without affecting the percentage of ATF + neurons. In ipsilateral L5 dorsal root ganglion neurons, spinal nerve ligation reduced the percentage of P2X3R + neurons and markedly increased the percentage of ATF3 + cells. Almost all of P2X3Rs were expressed in damaged (ATF3+) neurons. Electroacupuncture had no effect on spinal nerve ligation-induced changes in the percentage of P2X3R or percentage of ATF3 + cells in L5 dorsal root ganglia. These observations led us to conclude that electroacupuncture effectively reduces injury-induced chronic pain by selectively reducing the expression of P2X3Rs in nerve-uninjured L4 dorsal root ganglion neurons.
Collapse
Affiliation(s)
- Yi Liang
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch, Galveston, TX, USA
| | - Yanping Gu
- Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch, Galveston, TX, USA
| | - Renyi Shi
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Guangwen Li
- Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch, Galveston, TX, USA
| | - Yong Chen
- Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch, Galveston, TX, USA
| | - Li-Yen Mae Huang
- Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch, Galveston, TX, USA
| |
Collapse
|
29
|
Tang Y, Yin HY, Liu J, Rubini P, Illes P. P2X receptors and acupuncture analgesia. Brain Res Bull 2018; 151:144-152. [PMID: 30458249 DOI: 10.1016/j.brainresbull.2018.10.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 10/13/2018] [Accepted: 10/18/2018] [Indexed: 12/20/2022]
Abstract
Purinergic signaling has recently been suggested to constitute the cellular mechanism underlying acupuncture-induced analgesia (AA). By extending the original hypothesis on endogenous opioids being released during AA, Geoffrey Burnstock and Maiken Nedergaard supplied evidence for the involvement of purinoceptors (P2 and P1/A1 receptors) in the beneficial effects of AA. In view of certain pain states (e.g. neuropathic pain) which respond only poorly to therapy with standard analgesics, as well as with respect to the numerous unwanted effects of opioids and non-steroidal anti-inflammatory drugs, it is of great significance to search for alternative therapeutic options. Because clinical studies on AA yielded sometimes heterogeneous results, it is of eminent importance to relay on experiments carried out on laboratory animals, by evaluating the data with stringent statistical methods including comparison with a sufficient number of control groups. In this review, we summarize the state of the art situation with respect to the participation of P2 receptors in AA and try to forecast how the field is likely to move forward in the future.
Collapse
Affiliation(s)
- Yong Tang
- Medical & Nursing School, Chengdu University, 610106 Chengdu, China; Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, 610075 Chengdu, China.
| | - Hai-Yan Yin
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, 610075 Chengdu, China
| | - Juan Liu
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, 610075 Chengdu, China
| | - Patrizia Rubini
- Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Universität Leipzig, 04107 Leipzig, Germany
| | - Peter Illes
- Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Universität Leipzig, 04107 Leipzig, Germany; Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, 610075 Chengdu, China.
| |
Collapse
|
30
|
Transcriptomic profiling of trigeminal nucleus caudalis and spinal cord dorsal horn. Brain Res 2018; 1692:23-33. [DOI: 10.1016/j.brainres.2018.04.037] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 03/15/2018] [Accepted: 04/29/2018] [Indexed: 12/13/2022]
|
31
|
Park SH, Eber MR, Widner DB, Shiozawa Y. Role of the Bone Microenvironment in the Development of Painful Complications of Skeletal Metastases. Cancers (Basel) 2018; 10:cancers10050141. [PMID: 29747461 PMCID: PMC5977114 DOI: 10.3390/cancers10050141] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 05/07/2018] [Accepted: 05/08/2018] [Indexed: 01/02/2023] Open
Abstract
Cancer-induced bone pain (CIBP) is the most common and painful complication in patients with bone metastases. It causes a significant reduction in patient quality of life. Available analgesic treatments for CIBP, such as opioids that target the central nervous system, come with severe side effects as well as the risk of abuse and addiction. Therefore, alternative treatments for CIBP are desperately needed. Although the exact mechanisms of CIBP have not been fully elucidated, recent studies using preclinical models have demonstrated the role of the bone marrow microenvironment (e.g., osteoclasts, osteoblasts, macrophages, mast cells, mesenchymal stem cells, and fibroblasts) in CIBP development. Several clinical trials have been performed based on these findings. CIBP is a complex and challenging condition that currently has no standard effective treatments other than opioids. Further studies are clearly warranted to better understand this painful condition and develop more effective and safer targeted therapies.
Collapse
Affiliation(s)
- Sun H Park
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
| | - Matthew R Eber
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
| | - D Brooke Widner
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
| | - Yusuke Shiozawa
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
| |
Collapse
|
32
|
Akef HM. Anticancer, antimicrobial, and analgesic activities of spider venoms. Toxicol Res (Camb) 2018; 7:381-395. [PMID: 30090588 PMCID: PMC6060684 DOI: 10.1039/c8tx00022k] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 02/13/2018] [Indexed: 12/19/2022] Open
Abstract
Spider venoms are complex mixtures composed of a variety of compounds, including salts, small organic molecules, peptides, and proteins. But, the venom of a few species is dangerous to humans. High levels of chemical diversity make spider venoms attractive subjects for chemical prospecting. Many spider venom components show potential activity against a wide range of human diseases. However, the development of novel venom-derived therapeutics requires an understanding of their mechanisms of action. This review will highlight the structures, activities and the possible mechanisms of action of spider venoms and their components against cancer, microbial infections, and pain.
Collapse
Affiliation(s)
- Hassan M Akef
- National Organization for Research and Control of Biologicals (NORCB) , Giza , Egypt . ; ; Tel: +20-2-37480478
| |
Collapse
|
33
|
Do TP, Hvedstrup J, Schytz HW. Botulinum toxin: A review of the mode of action in migraine. Acta Neurol Scand 2018; 137:442-451. [PMID: 29405250 DOI: 10.1111/ane.12906] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/17/2018] [Indexed: 12/30/2022]
Abstract
Botulinum toxin serotype A (BoNT/A) was originally used in neurology for the treatment of dystonia and blepharospasms, but is now clinically used worldwide for the treatment of chronic migraine. Still, the possible mode of action of BoNT/A in migraine is not fully known. However, the mode of action of BoNT/A has been investigated in experimental pain as well as migraine models, which may elucidate the underlying mechanisms in migraine. The aim of this study was to review studies on the possible mode of action of BoNT/A in relation to chronic migraine treatment. Observations suggest that the mode of action of BoNT/A may not be limited to the injection site, but also includes anatomically connected sites due to axonal transport. The mechanisms behind the effect of BoNT/A in chronic migraine may also include modulation of neurotransmitter release, changes in surface expression of receptors and cytokines as well as enhancement of opioidergic transmission. Clinical and experimental studies with botulinum toxin in the last decade have advanced our understanding of headache and other pain states. More research into botulinum toxin as treatment for headache is warranted as it can be an attractive alternative for patients who do not respond positively to other drugs.
Collapse
Affiliation(s)
- T. P. Do
- Headache Diagnostic Laboratory; Danish Headache Center and Department of Neurology; Rigshospitalet-Glostrup; Faculty of Health Sciences, University of Copenhagen; Glostrup Denmark
| | - J. Hvedstrup
- Headache Diagnostic Laboratory; Danish Headache Center and Department of Neurology; Rigshospitalet-Glostrup; Faculty of Health Sciences, University of Copenhagen; Glostrup Denmark
| | - H. W. Schytz
- Headache Diagnostic Laboratory; Danish Headache Center and Department of Neurology; Rigshospitalet-Glostrup; Faculty of Health Sciences, University of Copenhagen; Glostrup Denmark
| |
Collapse
|
34
|
Stephan G, Huang L, Tang Y, Vilotti S, Fabbretti E, Yu Y, Nörenberg W, Franke H, Gölöncsér F, Sperlágh B, Dopychai A, Hausmann R, Schmalzing G, Rubini P, Illes P. The ASIC3/P2X3 cognate receptor is a pain-relevant and ligand-gated cationic channel. Nat Commun 2018; 9:1354. [PMID: 29636447 PMCID: PMC5893604 DOI: 10.1038/s41467-018-03728-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Accepted: 03/09/2018] [Indexed: 12/21/2022] Open
Abstract
Two subclasses of acid-sensing ion channels (ASIC3) and of ATP-sensitive P2X receptors (P2X3Rs) show a partially overlapping expression in sensory neurons. Here we report that both recombinant and native receptors interact with each other in multiple ways. Current measurements with the patch-clamp technique prove that ASIC3 stimulation strongly inhibits the P2X3R current partly by a Ca2+-dependent mechanism. The proton-binding site is critical for this effect and the two receptor channels appear to switch their ionic permeabilities during activation. Co-immunoprecipation proves the close association of the two protein structures. BN-PAGE and SDS-PAGE analysis is also best reconciled with the view that ASIC3 and P2X3Rs form a multiprotein structure. Finally, in vivo measurements in rats reveal the summation of pH and purinergically induced pain. In conclusion, the receptor subunits do not appear to form a heteromeric channel, but tightly associate with each other to form a protein complex, mediating unidirectional inhibition. Two subclasses of ligand-gated ion channels (ASIC3 and P2X3) are both present at sensory neurons and might be therefore subject to receptor crosstalk. Here authors use electrophysiology, biochemistry and co-immunoprecipitation to show that the two ion channels interact and affect P2X3 currents.
Collapse
Affiliation(s)
- Gabriele Stephan
- Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, University of Leipzig, Leipzig, 04107, Germany
| | - Lumei Huang
- Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, University of Leipzig, Leipzig, 04107, Germany.,Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Yong Tang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Sandra Vilotti
- Neurobiology Sector, International School for Advanced Studies, Trieste, 34136, Italy
| | - Elsa Fabbretti
- Department of Life Sciences, University of Trieste, Trieste, 34127, Italy
| | - Ye Yu
- Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai, 100025, China
| | - Wolfgang Nörenberg
- Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, University of Leipzig, Leipzig, 04107, Germany
| | - Heike Franke
- Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, University of Leipzig, Leipzig, 04107, Germany
| | - Flóra Gölöncsér
- Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, 1043, Hungary.,János Szentágothai School of Neurosciences, Semmelweis University School of PhD Studies, Budapest, 1043, Hungary
| | - Beáta Sperlágh
- Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, 1043, Hungary
| | - Anke Dopychai
- Molecular Pharmacology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, 52072, Germany
| | - Ralf Hausmann
- Molecular Pharmacology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, 52072, Germany
| | - Günther Schmalzing
- Molecular Pharmacology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, 52072, Germany
| | - Patrizia Rubini
- Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, University of Leipzig, Leipzig, 04107, Germany
| | - Peter Illes
- Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, University of Leipzig, Leipzig, 04107, Germany.
| |
Collapse
|
35
|
Wang W, Ma X, Luo L, Huang M, Dong J, Zhang X, Jiang W, Xu T. Exchange factor directly activated by cAMP-PKCε signalling mediates chronic morphine-induced expression of purine P2X3 receptor in rat dorsal root ganglia. Br J Pharmacol 2018; 175:1760-1769. [PMID: 29500928 DOI: 10.1111/bph.14191] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 02/22/2018] [Accepted: 02/23/2018] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND AND PURPOSE The P2X3 receptor is a major receptor in the processing of nociceptive information in dorsal root ganglia. We investigated the role of the P2X3 receptor and the detailed mechanisms underlying chronic morphine-induced analgesic tolerance in rats. EXPERIMENTAL APPROACH Repeated i.t. morphine treatment was used to induce anti-nociceptive tolerance. The expression of spinal P2X3 receptor, phosphorylated PKCε and exchange factor directly activated by cAMP (Epac) were evaluated. Effects of A-317491 (P2X3 antagonist), ε-V1-2 (PKCε inhibitor) and ESI-09 (Epac inhibitor) on mechanical pain thresholds and tail-flick latency after chronic morphine treatment were determined. Co-localization of P2X3 receptor with NeuNs (marker of neuron), IB4 (marker of small DRG neurons), peripherin, PKCε and Epac were performed by double immunofluorescence staining. KEY RESULTS Chronic morphine time-dependently increased the expression of P2X3 receptor, phosphorylated PKCε and Epac in DRGs. ε-V1-2 prevented chronic morphine-induced expression of P2X3 receptor. ESI-09 decreased the phosphorylation of PKCε and up-regulated expression of Epac after chronic morphine exposure. Mechanical pain thresholds and tail-flick latency showed that A317491, ε-V1-2 and ESI-09 significantly attenuated the loss of morphine's analgesic potency. Morphine-induced P2X3 receptor expression mainly occurred in neurons staining for IB4 and peripherin. Co-localization of P2X3 receptor with PKCε and Epac was demonstrated in the same neurons. CONCLUSIONS AND IMPLICATIONS Chronic morphine exposure increased the expression of P2X3 receptor, and i.t. P2X3 receptor antagonists attenuated the loss of morphine's analgesic effect. Inhibiting Epac/PKCε signalling was shown to play a significant inhibitory role in chronic morphine-induced P2X3 receptor expression and attenuate morphine-induced tolerance.
Collapse
Affiliation(s)
- Wenying Wang
- Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaqing Ma
- Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China.,Department of Anesthesiology, Nantong Third People's Hospital, Nantong University, Nantong, China
| | - Limin Luo
- Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Min Huang
- Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Dong
- Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoli Zhang
- Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Jiang
- Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Tao Xu
- Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China.,Department of Anesthesiology, Tongzhou People's Hospital, Nantong, China
| |
Collapse
|
36
|
Abstract
Most of the energy we get to spend is furnished by mitochondria, minuscule living structures sitting inside our cells or dispatched back and forth within them to where they are needed. Mitochondria produce energy by burning down what remains of our meal after we have digested it, but at the cost of constantly corroding themselves and us. Here we review how our mitochondria evolved from invading bacteria and have retained a small amount of independence from us; how we inherit them only from our mother; and how they are heavily implicated in learning, memory, cognition, and virtually every mental or neurological affliction. We discuss why counteracting mitochondrial corrosion with antioxidant supplements is often unwise, and why our mitochondria, and therefore we ourselves, benefit instead from exercise, meditation, sleep, sunshine, and particular eating habits. Finally, we describe how malfunctioning mitochondria force rats to become socially subordinate to others, how such disparity can be evened off by a vitamin, and why these findings are relevant to us.
Collapse
Affiliation(s)
- Peter Kramer
- Department of General Psychology, University of Padua, Italy
| | - Paola Bressan
- Department of General Psychology, University of Padua, Italy
| |
Collapse
|
37
|
Villarejo-López L, Jiménez E, Bartolomé-Martín D, Zafra F, Lapunzina P, Aragón C, López-Corcuera B. P2X receptors up-regulate the cell-surface expression of the neuronal glycine transporter GlyT2. Neuropharmacology 2017; 125:99-116. [PMID: 28734869 DOI: 10.1016/j.neuropharm.2017.07.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 07/11/2017] [Accepted: 07/17/2017] [Indexed: 12/27/2022]
Abstract
Glycinergic inhibitory neurons of the spinal dorsal horn exert critical control over the conduction of nociceptive signals to higher brain areas. The neuronal glycine transporter 2 (GlyT2) is involved in the recycling of synaptic glycine from the inhibitory synaptic cleft and its activity modulates intra and extracellular glycine concentrations. In this report we show that the stimulation of P2X purinergic receptors with βγ-methylene adenosine 5'-triphosphate induces the up-regulation of GlyT2 transport activity by increasing total and plasma membrane expression and reducing transporter ubiquitination. We identified the receptor subtypes involved by combining pharmacological approaches, siRNA-mediated protein knockdown, and dorsal root ganglion cell enrichment in brainstem and spinal cord primary cultures. Up-regulation of GlyT2 required the combined stimulation of homomeric P2X3 and P2X2 receptors or heteromeric P2X2/3 receptors. We measured the spontaneous glycinergic currents, glycine release and GlyT2 uptake concurrently in response to P2X receptor agonists, and showed that the impact of P2X3 receptor activation on glycinergic neurotransmission involves the modulation of GlyT2 expression or activity. The recognized pro-nociceptive action of P2X3 receptors suggests that the fine-tuning of GlyT2 activity may have consequences in nociceptive signal conduction.
Collapse
Affiliation(s)
- Lucía Villarejo-López
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Esperanza Jiménez
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain; IdiPAZ-Hospital Universitario La Paz, Madrid, Spain
| | - David Bartolomé-Martín
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
| | - Francisco Zafra
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain; IdiPAZ-Hospital Universitario La Paz, Madrid, Spain
| | - Pablo Lapunzina
- Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain; Instituto de Genética Médica y Molecular, IdiPAZ-Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid 28046, Spain
| | - Carmen Aragón
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain; IdiPAZ-Hospital Universitario La Paz, Madrid, Spain
| | - Beatriz López-Corcuera
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain; IdiPAZ-Hospital Universitario La Paz, Madrid, Spain.
| |
Collapse
|
38
|
Xiong W, Tan M, He L, Ou X, Jin Y, Yang G, Huang L, Shen Y, Guan S, Xu C, Li G, Liu S, Xu H, Liang S, Gao Y. Inhibitory effects of tetramethylpyrazine on pain transmission of trigeminal neuralgia in CCI-ION rats. Brain Res Bull 2017; 134:72-78. [PMID: 28710025 DOI: 10.1016/j.brainresbull.2017.07.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 06/04/2017] [Accepted: 07/06/2017] [Indexed: 12/21/2022]
Abstract
Tetramethylpyrazine (TMP) has anti-inflammatory effects and is used to treat cerebral ischemic injury, but the mechanism of TMP on neural protection is not clear. Trigeminal neuralgia (TN) is a facial pain syndrome that is characterized by paroxysmal, shock-like pain attacks located in the somatosensory distribution of the trigeminal nerve. P2X3 receptor plays a crucial role in facilitating pain transmission. The present study investigates the effects of TMP on trigeminal neuralgia transmission mediated by P2X3 receptor of the trigeminal ganglia (TG). Chronic constriction injury of the infraorbital branch of the trigeminal nerve (CCI-ION) was used as a trigeminal neuralgia model. On day 15 after surgery, there was a significant decline in the mechanical hyperalgesia threshold in the territory of the ligated infraorbital nerve in the TN group, and an increase in expression of P2X3 receptor in the TG of the TN group compared with the Sham group. After treatment with TMP or A-317491, the mechanical hyperalgesia threshold of TN rats was significantly higher, and expression of P2X3 receptor in the TG noticeably declined compared with the TN group. Phosphorylation of p38 and ERK1/2 in the TN group was stronger than in the Sham group. However, the phosphorylation of p38 and ERK1/2 in the TN+TMP group and TN+A-317491 group was much lower than in the TN group. TMP significantly inhibited the ATP activated currents in HEK293 cells transfected with a P2X3 plasmid. Thus, TMP might have inhibitory effects on trigeminal neuralgia by suppressing the expression of P2X3 receptor in the TG and the phosphorylation of p38 and ERK1/2 in the TG.
Collapse
Affiliation(s)
- Wei Xiong
- Affiliated Stomatological Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Mengxia Tan
- Department of Physiology, Medical College of Nanchang University, 461 Bayi Road, Nanchang, Jiangxi 330006, PR China
| | - Lingkun He
- Affiliated Stomatological Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Xiaoyan Ou
- Affiliated Stomatological Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Youhong Jin
- Affiliated Stomatological Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Guo Yang
- Queen Mary college of grade 2013, Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Liping Huang
- Department of Physiology, Medical College of Nanchang University, 461 Bayi Road, Nanchang, Jiangxi 330006, PR China
| | - Yulin Shen
- Department of Physiology, Medical College of Nanchang University, 461 Bayi Road, Nanchang, Jiangxi 330006, PR China
| | - Shu Guan
- Department of Physiology, Medical College of Nanchang University, 461 Bayi Road, Nanchang, Jiangxi 330006, PR China
| | - Changshui Xu
- Department of Physiology, Medical College of Nanchang University, 461 Bayi Road, Nanchang, Jiangxi 330006, PR China
| | - Guilin Li
- Department of Physiology, Medical College of Nanchang University, 461 Bayi Road, Nanchang, Jiangxi 330006, PR China
| | - Shuangmei Liu
- Department of Physiology, Medical College of Nanchang University, 461 Bayi Road, Nanchang, Jiangxi 330006, PR China
| | - Hong Xu
- Department of Physiology, Medical College of Nanchang University, 461 Bayi Road, Nanchang, Jiangxi 330006, PR China
| | - Shangdong Liang
- Department of Physiology, Medical College of Nanchang University, 461 Bayi Road, Nanchang, Jiangxi 330006, PR China.
| | - Yun Gao
- Department of Physiology, Medical College of Nanchang University, 461 Bayi Road, Nanchang, Jiangxi 330006, PR China.
| |
Collapse
|
39
|
Nascimento DSM, Potes CS, Soares ML, Ferreira AC, Malcangio M, Castro-Lopes JM, Neto FLM. Drug-Induced HSP90 Inhibition Alleviates Pain in Monoarthritic Rats and Alters the Expression of New Putative Pain Players at the DRG. Mol Neurobiol 2017; 55:3959-3975. [PMID: 28550532 DOI: 10.1007/s12035-017-0628-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 05/19/2017] [Indexed: 01/17/2023]
Abstract
Purinergic receptors (P2XRs) have been widely associated with pain states mostly due to their involvement in neuron-glia communication. Interestingly, we have previously shown that satellite glial cells (SGC), surrounding dorsal root ganglia (DRG) neurons, become activated and proliferate during monoarthritis (MA) in the rat. Here, we demonstrate that P2X7R expression increases in ipsilateral DRG after 1 week of disease, while P2X3R immunoreactivity decreases. We have also reported a significant induction of the activating transcriptional factor 3 (ATF3) in MA. In this study, we show that ATF3 knocked down in DRG cell cultures does not affect the expression of P2X7R, P2X3R, or glial fibrillary acidic protein (GFAP). We suggest that P2X7R negatively regulates P2X3R, which, however, is unlikely mediated by ATF3. Interestingly, we found that ATF3 knockdown in vitro induced significant decreases in the heat shock protein 90 (HSP90) expression. Thus, we evaluated in vivo the involvement of HSP90 in MA and demonstrated that the HSP90 messenger RNA levels increase in ipsilateral DRG of inflamed animals. We also show that HSP90 is mostly found in a cleaved form in this condition. Moreover, administration of a HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), attenuated MA-induced mechanical allodynia in the first hours. The drug also reversed the HSP90 upregulation and cleavage. 17-DMAG seemed to attenuate glial activation and neuronal sensitization (as inferred by downregulation of GFAP and P2X3R in ipsilateral DRG) which might correlate with the observed pain alleviation. Our data indicate a role of HSP90 in MA pathophysiology, but further investigation is necessary to clarify the underlying mechanisms.
Collapse
Affiliation(s)
- Diana Sofia Marques Nascimento
- Departamento de Biomedicina-Unidade de Biologia Experimental, Centro de Investigação Médica (CIM), Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Pain Group, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Catarina Soares Potes
- Departamento de Biomedicina-Unidade de Biologia Experimental, Centro de Investigação Médica (CIM), Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Pain Group, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Miguel Luz Soares
- Departamento de Biomedicina-Unidade de Biologia Experimental, Centro de Investigação Médica (CIM), Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Pain Group, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Laboratório de Apoio à Investigação em Medicina Molecular (LAIMM), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - António Carlos Ferreira
- Departamento de Biomedicina-Unidade de Biologia Experimental, Centro de Investigação Médica (CIM), Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Pain Group, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Laboratório de Apoio à Investigação em Medicina Molecular (LAIMM), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Marzia Malcangio
- Wolfson Centre for Age Related Diseases, King's College London, London, UK
| | - José Manuel Castro-Lopes
- Departamento de Biomedicina-Unidade de Biologia Experimental, Centro de Investigação Médica (CIM), Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Pain Group, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Fani Lourença Moreira Neto
- Departamento de Biomedicina-Unidade de Biologia Experimental, Centro de Investigação Médica (CIM), Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal. .,Pain Group, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal. .,Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
| |
Collapse
|
40
|
On the permeation of large organic cations through the pore of ATP-gated P2X receptors. Proc Natl Acad Sci U S A 2017; 114:E3786-E3795. [PMID: 28442564 DOI: 10.1073/pnas.1701379114] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Pore dilation is thought to be a hallmark of purinergic P2X receptors. The most commonly held view of this unusual process posits that under prolonged ATP exposure the ion pore expands in a striking manner from an initial small-cation conductive state to a dilated state, which allows the passage of larger synthetic cations, such as N-methyl-d-glucamine (NMDG+). However, this mechanism is controversial, and the identity of the natural large permeating cations remains elusive. Here, we provide evidence that, contrary to the time-dependent pore dilation model, ATP binding opens an NMDG+-permeable channel within milliseconds, with a conductance that remains stable over time. We show that the time course of NMDG+ permeability superimposes that of Na+ and demonstrate that the molecular motions leading to the permeation of NMDG+ are very similar to those that drive Na+ flow. We found, however, that NMDG+ "percolates" 10 times slower than Na+ in the open state, likely due to a conformational and orientational selection of permeating molecules. We further uncover that several P2X receptors, including those able to desensitize, are permeable not only to NMDG+ but also to spermidine, a large natural cation involved in ion channel modulation, revealing a previously unrecognized P2X-mediated signaling. Altogether, our data do not support a time-dependent dilation of the pore on its own but rather reveal that the open pore of P2X receptors is wide enough to allow the permeation of large organic cations, including natural ones. This permeation mechanism has considerable physiological significance.
Collapse
|
41
|
Abstract
Protein kinase C alpha plays a major role in mediating Epac-dependent enhancement of purinergic P2X3R activity in dorsal root ganglion neurons after inflammation. Sensitization of purinergic P2X3 receptors (P2X3Rs) is a major mechanism contributing to injury-induced exaggerated pain responses. We showed in a previous study that cyclic adenosine monophosphate (cAMP)–dependent guanine nucleotide exchange factor 1 (Epac1) in rat sensory dorsal root ganglia (DRGs) is upregulated after inflammatory injury, and it plays a critical role in P2X3R sensitization by activating protein kinase C epsilon (PKCε) inside the cells. protein kinase C epsilon has been established as the major PKC isoform mediating injury-induced hyperalgesic responses. On the other hand, the role of PKCα in receptor sensitization was seldom considered. Here, we studied the participation of PKCα in Epac signaling in P2X3R-mediated hyperalgesia. The expression of both Epac1 and Epac2 and the level of cAMP in DRGs are greatly enhanced after complete Freund adjuvant (CFA)–induced inflammation. The expression of phosphorylated PKCα is also upregulated. Complete Freund adjuvant (CFA)–induced P2X3R-mediated hyperalgesia is not only blocked by Epac antagonists but also by the classical PKC isoform inhibitors, Go6976, and PKCα-siRNA. These CFA effects are mimicked by the application of the Epac agonist, 8-(4-chlorophenylthio)-2 -O-methyl-cAMP (CPT), in control rats, further confirming the involvement of Epacs. Because the application of Go6976 prior to CPT still reduces CPT-induced hyperalgesia, PKCα is downstream of Epacs to mediate the enhancement of P2X3R responses in DRGs. The pattern of translocation of PKCα inside DRG neurons in response to CPT or CFA stimulation is distinct from that of PKCε. Thus, in contrast to prevalent view, PKCα also plays an essential role in producing complex inflammation-induced receptor-mediated hyperalgesia.
Collapse
|
42
|
Dal Ben D, Marchenkova A, Thomas A, Lambertucci C, Spinaci A, Marucci G, Nistri A, Volpini R. 2',3'-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents. Purinergic Signal 2017; 13:61-74. [PMID: 27757785 PMCID: PMC5334199 DOI: 10.1007/s11302-016-9539-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 09/19/2016] [Indexed: 11/29/2022] Open
Abstract
Blocking membrane currents evoked by the activation of purinergic P2X3 receptors localized on nociceptive neurons represents a promising strategy for the development of agents useful for the treatment of chronic pain conditions. Among compounds endowed with such antagonistic action, 2',3'-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP) is an ATP analogue, whose inhibitory activity on P2X receptors has been previously reported. Based on the results of molecular modelling studies performed with homology models of the P2X3 receptor, novel adenosine nucleotide analogues bearing cycloalkyl or arylalkyl substituents replacing the trinitrophenyl moiety of TNP-ATP were designed and synthesized. These new compounds were functionally evaluated on native P2X3 receptors from mouse trigeminal ganglion (TG) sensory neurons using patch clamp recordings under voltage clamp configuration. Our data show that some of these molecules are potent (nanomolar range) and reversible inhibitors of P2X3 receptors, without any apparent effect on trigeminal GABAA and 5-HT3 receptors, whose membrane currents were unaffected by the tested compounds.
Collapse
Affiliation(s)
- Diego Dal Ben
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, (MC), Italy
| | - Anna Marchenkova
- Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136, Trieste, Italy
| | - Ajiroghene Thomas
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, (MC), Italy
| | - Catia Lambertucci
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, (MC), Italy
| | - Andrea Spinaci
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, (MC), Italy
| | - Gabriella Marucci
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, (MC), Italy
| | - Andrea Nistri
- Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136, Trieste, Italy
| | - Rosaria Volpini
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, (MC), Italy.
| |
Collapse
|
43
|
He YQ, Lang XQ, Lin L, Ji L, Yuan XY, Chen Q, Ran YM, Chen HS, Li L, Wang JM, Wang ZG, Gregersen H, Zou DW, Liang HP, Yang M. P2X3 receptor-mediated visceral hyperalgesia and neuronal sensitization following exposure to PTSD-like stress in the dorsal root ganglia of rats. Neurogastroenterol Motil 2017; 29. [PMID: 27781340 DOI: 10.1111/nmo.12976] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 09/22/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND Patients with posttraumatic stress disorder (PTSD) often share co-morbidity with chronic pain conditions. Recent studies suggest a role of P2X3 receptors and ATP signaling in pain conditions. However, the underlying mechanisms of visceral hyperalgesia following exposure to PTSD-like stress conditions remain unclarified. METHODS The behavior and hormones relevant for PTSD were studied. Visceromotor responses (VMR) and the abdominal withdrawal reflexes (AWR) to colorectal distention (CRD) were recorded to determine P2X3-receptor-mediated alteration of hyperalgesia following single-prolonged stress (SPS) exposure. Immunofluorescence, Western blotting, and patch-clamp were used. KEY RESULTS The escape latency, adrenocorticotropic hormone and cortisol were increased on days 7-14. Visceromotor responses and AWR was reduced at day 1 in SPS rats but increased to higher levels than in controls after exposure to day 7. Intrathecal administration of the P2X3-receptor antagonist TNP-ATP abolished the CRD response. Based on immunofluorescence and Western blotting analysis, SPS-treated rats exhibited reduced P2X3 expression in dorsal root ganglia (DRG) after day 1 compared with controls. P2X3 expression in DRG was enhanced on day 7 after SPS and the increase of the P2X3 expression was maintained on day 14 and 21 compared with controls. The P2X3-receptor agonist α,β-me ATP (10 μM) induced a fast desensitizing inward current in DRG neurons of both control and SPS-treated rats. The average peak current densities in SPS-treated group were increased 3.6-fold. TNP-ATP (100 nM) markedly blocked all fast α,β-me ATP-induced inward currents in the DRG neurons both in control and SPS-treated rats. CONCLUSIONS & INFERENCES The data indicate an important role of P2X3 signaling in visceral hyperalgesia following PTSD-like stress.
Collapse
Affiliation(s)
- Y-Q He
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - X-Q Lang
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - L Lin
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - L Ji
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - X-Y Yuan
- Department of Gastroenterology, The Ninth People's Hospital of Chongqing, Chongqing, China
| | - Q Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Y-M Ran
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - H-S Chen
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, China
| | - L Li
- Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - J-M Wang
- Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Z-G Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China.,Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - H Gregersen
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College of Chongqing University, Chongqing, China
| | - D-W Zou
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - H-P Liang
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China.,Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - M Yang
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China.,Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| |
Collapse
|
44
|
Liu X, Ma L, Zhang S, Ren Y, Dirksen RT. CD73 Controls Extracellular Adenosine Generation in the Trigeminal Nociceptive Nerves. J Dent Res 2017; 96:671-677. [PMID: 28530470 DOI: 10.1177/0022034517692953] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Purinergic signaling is involved in pain generation and modulation in the nociceptive sensory nervous system. Adenosine triphosphate (ATP) induces pain via activation of ionotropic P2X receptors while adenosine mediates analgesia via activation of metabotropic P1 receptors. These purinergic signaling are determined by ecto-nucleotidases that control ATP degradation and adenosine generation. Using enzymatic histochemistry, we detected ecto-AMPase activity in dental pulp, trigeminal ganglia (TG) neurons, and their nerve fibers. Using immunofluorescence staining, we confirmed the expression of ecto-5'-nucleotidase (CD73) in trigeminal nociceptive neurons and their axonal fibers, including the nociceptive nerve fibers projecting into the brainstem. In addition, we detected the existence of CD73 and ecto-AMPase activity in the nociceptive lamina of the trigeminal subnucleus caudalis (TSNC) in the brainstem. Furthermore, we demonstrated that incubation with specific anti-CD73 serum significantly reduced the ecto-AMPase activity in the nociceptive lamina in the brainstem. Our results indicate that CD73 might participate in nociceptive modulation by affecting extracellular adenosine generation in the trigeminal nociceptive pathway. Disruption of TG neuronal ecto-nucleotidase expression and axonal terminal localization under certain circumstances such as chronic inflammation, oxidant stress, local constriction, and injury in trigeminal nerves may contribute to the pathogenesis of orofacial neuropathic pain.
Collapse
Affiliation(s)
- X Liu
- 1 Department of Dentistry, Eastman Institute for Oral Health, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.,2 Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - L Ma
- 1 Department of Dentistry, Eastman Institute for Oral Health, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.,3 Department of Dentistry, School of Stomatology, Zhengzhou University, Zhengzhou, China
| | - S Zhang
- 1 Department of Dentistry, Eastman Institute for Oral Health, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Y Ren
- 1 Department of Dentistry, Eastman Institute for Oral Health, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - R T Dirksen
- 2 Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| |
Collapse
|
45
|
Synergistic combinations of the dual enkephalinase inhibitor PL265 given orally with various analgesic compounds acting on different targets, in a murine model of cancer-induced bone pain. Scand J Pain 2016; 14:25-38. [PMID: 28850427 DOI: 10.1016/j.sjpain.2016.09.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 09/14/2016] [Accepted: 09/30/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND The first line pharmacological treatment of cancer pain is morphine and surrogates but a significant pain relief and a reduction of the side-effects of these compounds makes it necessary to combine them with other drugs acting on different targets. The aim of this study was to measure the antinociceptive effect on cancer-induced bone pain resulting from the association of the endogenous opioids enkephalin and non-opioid analgesic drugs. For this purpose, PL265 a new orally active single dual inhibitor of the two degrading enkephalins enzymes, neprilysin (NEP) and aminopeptidase N (APN) was used. It strictly increased the levels of enkephalin at their sites of releases. The selected non-opioid compounds are: gabapentin, A-317491 (P2X3 receptor antagonist), ACEA (CB1 receptor antagonist), AM1241 (CB2 receptor antagonist), JWH-133 (CB2 receptor antagonist), URB937 (FAAH inhibitor), and NAV26 (Nav1.7 channel blocker). METHODS Experiments. Experiments were performed in 5-6 weeks old (26-33g weight) C57BL/6 mice. Cell culture and cell inoculation. B16-F10 melanoma cells were cultured and when preconfluent, treated and detached. Finally related cells were resuspended to obtain a concentration of 2×106 cells/100μL. Then 105 cells were injected into the right tibial medullar cavity. Control mice were treated by killed cells by freezing. Behavioural studies. Thermal withdrawal latencies were measured on a unilatered hot plate (UHP) maintained at 49±0.2°C. Mechanical threshold values were obtained by performing the von Frey test using the "up and down" method. To evaluate the nature (additive or synergistic) of the interactions between PL265 and different drugs, an isobolographic analysis following the method described by Tallarida was performed. RESULTS The results demonstrate the ability of PL265, a DENKI that prevents the degradation of endogenous ENKs, to counteract cancer-induced bone thermal hyperalgesia in mice, by exclusively stimulating peripheral opioid receptors as demonstrated by used of an opioid antagonist unable to enter the brain. The development of such DENKIs, endowed with druggable pharmacokinetic characteristics, such as good absorption by oral route, can be considered as an important step in the development of much needed novel antihyperalgesic drugs. Furthermore, all the tested combinations resulted in synergistic antihyperalgesic effects. As shown here, the greatest synergistic antinociceptive effect (doses could be lowered by 70%) was produced by the combination of PL265 with the P2X3 receptor antagonist (A-317491), cannabinoid CB1 receptor agonist (exogenous, ACEA and endogenous URB937-protected-AEA) and Nav1.7 blocker (NAV26) whose mechanism of action involves the direct activation of the enkephalinergic system. CONCLUSIONS These multi-target-based antinociceptive strategies using combinations of non-opioid drugs with dual inhibitors of enkephalin degrading enzymes may bring therapeutic advantages in terms of efficacy and safety by allowing the reduction of doses of one of the compounds or of both, which is of the utmost interest in the chronic treatment of cancer pain. IMPLICATIONS This article presents synergistic antinociceptive effect produced by the combination of PL265 with non-opioid analgesic drugs acting via unrelated mechanisms. These multi-target-based antinociceptive strategies may bring therapeutic advantages by allowing the reduction of doses, which is of great interest in the chronic treatment of cancer pain.
Collapse
|
46
|
Zhu Y, Wang S, Long H, Zhu J, Jian F, Ye N, Lai W. Effect of static magnetic field on pain level and expression of P2X3 receptors in the trigeminal ganglion in mice following experimental tooth movement. Bioelectromagnetics 2016; 38:22-30. [PMID: 27770441 DOI: 10.1002/bem.22009] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 09/10/2016] [Indexed: 02/05/2023]
Affiliation(s)
- Yafen Zhu
- Department of Orthodontics; State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University; Chengdu China
| | - Shengguo Wang
- Department of Stomatology; Second Affiliated Hospital; Chongqing Medical University; Chongqing China
| | - Hu Long
- Department of Orthodontics; State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University; Chengdu China
| | - Jingyi Zhu
- Department of Orthodontics; State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University; Chengdu China
| | - Fan Jian
- Department of Orthodontics; State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University; Chengdu China
| | - Niansong Ye
- Department of Orthodontics; Ninth People's Hospital; Shanghai Jiao Tong University; Shanghai China
| | - Wenli Lai
- Department of Orthodontics; State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University; Chengdu China
| |
Collapse
|
47
|
Ma L, Trinh T, Ren Y, Dirksen RT, Liu X. Neuronal NTPDase3 Mediates Extracellular ATP Degradation in Trigeminal Nociceptive Pathway. PLoS One 2016; 11:e0164028. [PMID: 27706204 PMCID: PMC5051867 DOI: 10.1371/journal.pone.0164028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 09/19/2016] [Indexed: 01/05/2023] Open
Abstract
ATP induces pain via activation of purinergic receptors in nociceptive sensory nerves. ATP signaling is terminated by ATP hydrolysis mediated by cell surface-localized ecto-nucleotidases. Using enzymatic histochemical staining, we show that ecto-ATPase activity is present in mouse trigeminal nerves. Using immunofluorescence staining, we found that ecto-NTPDase3 is expressed in trigeminal nociceptive neurons and their projections to the brainstem. In addition, ecto-ATPase activity and ecto-NTPDase3 are also detected in the nociceptive outermost layer of the trigeminal subnucleus caudalis. Furthermore, we demonstrate that incubation with anti-NTPDase3 serum reduces extracellular ATP degradation in the nociceptive lamina of both the trigeminal subnucleus caudalis and the spinal cord dorsal horn. These results are consistent with neuronal NTPDase3 activity modulating pain signal transduction and transmission by affecting extracellular ATP hydrolysis within the trigeminal nociceptive pathway. Thus, disruption of trigeminal neuronal NTPDase3 expression and localization to presynaptic terminals during chronic inflammation, local constriction and injury may contribute to the pathogenesis of orofacial neuropathic pain.
Collapse
Affiliation(s)
- Lihua Ma
- Department of Dentistry, Eastman Institute for Oral Health, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States of America
- Department of Dentistry, School of Stomatology, Zhengzhou University, Zhengzhou, China
| | - Thu Trinh
- Department of Dentistry, Eastman Institute for Oral Health, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States of America
| | - Yanfang Ren
- Department of Dentistry, Eastman Institute for Oral Health, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States of America
| | - Robert T. Dirksen
- Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States of America
| | - Xiuxin Liu
- Department of Dentistry, Eastman Institute for Oral Health, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States of America
- Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States of America
- * E-mail:
| |
Collapse
|
48
|
Botz B, Bölcskei K, Helyes Z. Challenges to develop novel anti-inflammatory and analgesic drugs. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2016; 9. [PMID: 27576790 DOI: 10.1002/wnan.1427] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 07/21/2016] [Accepted: 07/30/2016] [Indexed: 12/11/2022]
Abstract
Chronic inflammatory diseases and persistent pain of different origin represent common medical, social, and economic burden, and their pharmacotherapy is still an unresolved issue. Therefore, there is a great and urgent need to develop anti-inflammatory and analgesic agents with novel mechanisms of action, but it is a very challenging task. The main problem is the relatively large translational gap between the preclinical experimental data and the clinical results due to characteristics of the models, difficulties with the investigational techniques particularly for pain, as well as species differences in the mechanisms. We summarize here the current state-of-the-art medication and related ongoing strategies, and the novel targets with lead molecules under clinical development. The first members of the gold-standard categories, such as nonsteroidal anti-inflammatory drugs, glucocorticoids, and opioids, were introduced decades ago, and since then very few drugs with novel mechanisms of action have been successfully taken to the clinics despite considerable development efforts. Several biologics targeting different key molecules have provided breakthrough in some autoimmune/inflammatory diseases, but they are expensive, only parenterally available, their long-term side effects often limit their administration, and they do not effectively reduce pain. Some kinase inhibitors and phosphodiesterase-4 blockers have recently been introduced as new directions. There are in fact some promising novel approaches at different clinical stages of drug development focusing on transient receptor potential vanilloid 1/ankyrin 1 channel antagonism, inhibition of voltage-gated sodium/calcium channels, several enzymes (kinases, semicarbazide-sensitive amine oxidases, and matrix metalloproteinases), cytokines/chemokines, transcription factors, nerve growth factor, and modulation of several G protein-coupled receptors (cannabinoids, purinoceptors, and neuropeptides). WIREs Nanomed Nanobiotechnol 2017, 9:e1427. doi: 10.1002/wnan.1427 For further resources related to this article, please visit the WIREs website.
Collapse
Affiliation(s)
- Bálint Botz
- Department of Radiology, Faculty of Medicine, University of Pécs, Pécs, Hungary.,János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Kata Bölcskei
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary.,Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary
| | - Zsuzsanna Helyes
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary.,Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary.,MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine, University of Pécs, Pécs, Hungary
| |
Collapse
|
49
|
Yegutkin GG, Guerrero-Toro C, Kilinc E, Koroleva K, Ishchenko Y, Abushik P, Giniatullina R, Fayuk D, Giniatullin R. Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions. Purinergic Signal 2016; 12:561-74. [PMID: 27369815 DOI: 10.1007/s11302-016-9521-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Accepted: 06/23/2016] [Indexed: 11/26/2022] Open
Abstract
Extracellular ATP is suspected to contribute to migraine pain but regulatory mechanisms controlling pro-nociceptive purinergic mechanisms in the meninges remain unknown. We studied the peculiarities of metabolic and signaling pathways of ATP and its downstream metabolites in rat meninges and in cultured trigeminal cells exposed to the migraine mediator calcitonin gene-related peptide (CGRP). Under resting conditions, meningeal ATP and ADP remained at low nanomolar levels, whereas extracellular AMP and adenosine concentrations were one-two orders higher. CGRP increased ATP and ADP levels in meninges and trigeminal cultures and reduced adenosine concentration in trigeminal cells. Degradation rates for exogenous nucleotides remained similar in control and CGRP-treated meninges, indicating that CGRP triggers nucleotide release without affecting nucleotide-inactivating pathways. Lead nitrate-based enzyme histochemistry of whole mount meninges revealed the presence of high ATPase, ADPase, and AMPase activities, primarily localized in the medial meningeal artery. ATP and ADP induced large intracellular Ca(2+) transients both in neurons and in glial cells whereas AMP and adenosine were ineffective. In trigeminal glia, ATP partially operated via P2X7 receptors. ATP, but not other nucleotides, activated nociceptive spikes in meningeal trigeminal nerve fibers providing a rationale for high degradation rate of pro-nociceptive ATP. Pro-nociceptive effect of ATP in meningeal nerves was reproduced by α,β-meATP operating via P2X3 receptors. Collectively, extracellular ATP, which level is controlled by CGRP, can persistently activate trigeminal nerves in meninges which considered as the origin site of migraine headache. These data are consistent with the purinergic hypothesis of migraine pain and suggest new targets against trigeminal pain.
Collapse
Affiliation(s)
| | - Cindy Guerrero-Toro
- Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, P.O. Box 1627, 70211, Kuopio, Finland
| | - Erkan Kilinc
- Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, P.O. Box 1627, 70211, Kuopio, Finland
- Department of Physiology, Medical Faculty, Abant Izzet Baysal University, Bolu, Turkey
| | - Kseniya Koroleva
- Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, P.O. Box 1627, 70211, Kuopio, Finland
- Kazan Federal University, Kazan, Russia
| | - Yevheniia Ishchenko
- Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, P.O. Box 1627, 70211, Kuopio, Finland
| | - Polina Abushik
- Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, P.O. Box 1627, 70211, Kuopio, Finland
| | - Raisa Giniatullina
- Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, P.O. Box 1627, 70211, Kuopio, Finland
| | - Dmitriy Fayuk
- Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, P.O. Box 1627, 70211, Kuopio, Finland
| | - Rashid Giniatullin
- Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, P.O. Box 1627, 70211, Kuopio, Finland.
- Kazan Federal University, Kazan, Russia.
| |
Collapse
|
50
|
Tang Y, Yin HY, Rubini P, Illes P. Acupuncture-Induced Analgesia: A Neurobiological Basis in Purinergic Signaling. Neuroscientist 2016; 22:563-578. [PMID: 27343858 DOI: 10.1177/1073858416654453] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Chronic pain is a debilitating and rather common health problem. The present shortage in analgesic drugs with a favorable spectrum but without remarkable side effects furthered the search for alternative therapeutic manipulations. Increasing evidence from both basic and clinical research on acupuncture, a main alternative therapy of traditional Chinese medicine, suggests that chronic pain is sensitive to acupuncture procedures. Clarification of the underlying mechanisms is a challenge of great theoretical and practical significance. The seminal hypothesis of Geoffrey Burnstock and the astounding findings of Maiken Nedergaard on the involvement of purinergic signaling in the beneficial effects of acupuncture fertilized the field and led to an intensification of research on acupurines. In this review, we will summarize the state-of-the-art situation and try to forecast how the field is likely to develop in the future.
Collapse
Affiliation(s)
- Yong Tang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hai-Yan Yin
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Patrizia Rubini
- Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Universität Leipzig, Leipzig, Germany
| | - Peter Illes
- Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Universität Leipzig, Leipzig, Germany
| |
Collapse
|