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Wang Y, Yang L, Wu Y. Case report: Cheek acupuncture exhibits an immediate effect in relieving severe pain associated with nerve compression or damage of central nervous system and its potential mechanism of action. Front Neurosci 2023; 17:1211361. [PMID: 37547149 PMCID: PMC10400715 DOI: 10.3389/fnins.2023.1211361] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 05/26/2023] [Indexed: 08/08/2023] Open
Abstract
Peripheral nerve compression or permanent damage of central nervous system (CNS) can trigger severe neuralgia to patients. Analgesic medicine or even surgery to remove nerve compression is commonly used for pain relief. But these treatments either are ineffective, have side-effect or can cause subsequent complications. Acupuncture, a technique that has been widely used in China and other Asian countries for thousands of years, is an alternative to relieve pain, although the mechanism of action is not fully understood. In this study, two patients who had symptoms of severe neuralgia associated with peripheral nerve compression or permanent damage/dysfunction of CNS and analgesic medicines are ineffective, underwent cheek acupuncture, a new technique established recent years by the author with the features of painless, standardization, simplicity, and precision. An immediate analgesic effect of the cheek acupuncture was observed without any side effects, and clinical remission was achieved after several sessions of treatments. It suggests that this new approach is an efficient alternative for pain relief induced by nerve impairment. The authors proposed a biological holographic model of triplet homunculi existing at the level of the local cheek, spinal cord, and cerebral cortex, to explain the immediate and accurate analgesic effect of the cheek acupuncture. These homunculi have the same structure, and synchronized sensations and actions that are mediated by afferent and efferent neurons, as the integrated human body. Therefore, the nociception and needling signals are sensed, transmitted, analyzed, and manipulated cooperatively and simultaneously among these homunculi with the subsequent pain relief in the body.
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Affiliation(s)
- Yongzhou Wang
- International Cheek Acupuncture Therapy Institute, Fontenay-sous-Bois, France
| | - Lu Yang
- Department of Anesthesiology, Beijing United Family Hospital, Beijing, China
| | - Yongzheng Wu
- Unité de Biologie Cellulaire & Infection Microbienne, CNRS UMR3691, Institut Pasteur, Université Paris Cité, Paris, France
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Tjen-A-Looi SC, Fu LW, Guo ZL, Gong YD, Nguyen ATN, Nguyen ATP, Malik S. Neurogenic Hypotension and Bradycardia Modulated by Electroacupuncture in Hypothalamic Paraventricular Nucleus. Front Neurosci 2022; 16:934752. [PMID: 35958987 PMCID: PMC9361000 DOI: 10.3389/fnins.2022.934752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 06/23/2022] [Indexed: 11/13/2022] Open
Abstract
Electroacupuncture (EA) stimulates somatic median afferents underlying P5-6 acupoints and modulates parasympathoexcitatory reflex responses through central processing in the brainstem. Although decreases in blood pressure and heart rate by the neural-mediated Bezold-Jarisch reflex responses are modulated by EA through opioid actions in the nucleus tractus solitarius and nucleus ambiguus, the role of the hypothalamus is unclear. The hypothalamic paraventricular nucleus (PVN) is activated by sympathetic afferents and regulates sympathetic outflow and sympathoexcitatory cardiovascular responses. In addition, the PVN is activated by vagal afferents, but little is known about its regulation of cardiopulmonary inhibitory hemodynamic responses. We hypothesized that the PVN participates in the Bezold-Jarisch reflex responses and EA inhibits these cardiopulmonary responses through the PVN opioid system. Rats were anesthetized and ventilated, and their heart rate and blood pressures were monitored. Application of phenylbiguanide every 10 min close to the right atrium induced consistent depressor and bradycardia reflex responses. Unilateral microinjection of the depolarization blockade agent kainic acid or glutamate receptor antagonist kynurenic acid in the PVN reduced these reflex responses. In at least 70% of the rats, 30 min of bilateral EA at P5-6 acupoints reduced the depressor and bradycardia responses for at least 60 min. Blockade of the CCK-1 receptors converted the non-responders into EA-responders. Unilateral PVN-microinjection with naloxone reversed the EA inhibition. Vagal-evoked activity of the PVN cardiovascular neurons was reduced by 30 min EA (P5-6) through opioid receptor activation. These data indicate that PVN processes inhibitory cardiopulmonary reflexes and participates in EA-modulation of the neural-mediated vasodepression and bradycardia.
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Kaczyńska K, Wojciechowski P. Non-Opioid Peptides Targeting Opioid Effects. Int J Mol Sci 2021; 22:13619. [PMID: 34948415 PMCID: PMC8709238 DOI: 10.3390/ijms222413619] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/13/2021] [Accepted: 12/17/2021] [Indexed: 01/07/2023] Open
Abstract
Opioids are the most potent widely used analgesics, primarily, but not exclusively, in palliative care. However, they are associated with numerous side effects, such as tolerance, addiction, respiratory depression, and cardiovascular events. This, in turn, can result in their overuse in cases of addiction, the need for dose escalation in cases of developing tolerance, and the emergence of dose-related opioid toxicity, resulting in respiratory depression or cardiovascular problems that can even lead to unintentional death. Therefore, a very important challenge for researchers is to look for ways to counteract the side effects of opioids. The use of peptides and their related compounds, which have been shown to modulate the effects of opioids, may provide such an opportunity. This short review is a compendium of knowledge about the most important and recent findings regarding selected peptides and their modulatory effects on various opioid actions, including cardiovascular and respiratory responses. In addition to the peptides more commonly reported in the literature in the context of their pro- and/or anti-opioid activity-such as neuropeptide FF (NPFF), cholecystokinin (CCK), and melanocyte inhibiting factor (MIF)-we also included in the review nociceptin/orphanin (N/OFQ), ghrelin, oxytocin, endothelin, and venom peptides.
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Affiliation(s)
- Katarzyna Kaczyńska
- Department of Respiration Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego 5 St., 02-106 Warsaw, Poland;
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Lv Q, Wu F, Gan X, Yang X, Zhou L, Chen J, He Y, Zhang R, Zhu B, Liu L. The Involvement of Descending Pain Inhibitory System in Electroacupuncture-Induced Analgesia. Front Integr Neurosci 2019; 13:38. [PMID: 31496944 PMCID: PMC6712431 DOI: 10.3389/fnint.2019.00038] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 07/30/2019] [Indexed: 12/12/2022] Open
Abstract
Chronic pain is a major health problem, which can impair quality of life and reduce productivity. Electroacupuncture (EA), a modality of medicine based on the theories of Traditional Chinese Medicine (TCM), presents great therapeutic effects on chronic pain. Its clinical application has gained increasing popularity, and in parallel, more research has been performed on the mechanisms of EA-induced analgesia. The past decades have seen enormous advances both in neuronal circuitry of needle-insertion and in its molecular mechanism. EA may block pain by activating the descending pain inhibitory system, which originates in the brainstem and terminates at the spinal cord. This review article synthesizes corresponding studies to elucidate how EA alleviate pain via the mediation of this descending system. Much emphasis has been put on the implication of descending serotonergic and noradrenergic pathways in the process of pain modulation. Also, other important transmitters and supraspinal regions related to analgesic effects of EA have been demonstrated. Finally, it should be noticed that there exist some shortcomings involved in the animal experimental designed for EA, which account for conflicting results obtained by different studies.
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Affiliation(s)
- Qiuyi Lv
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Fengzhi Wu
- Journal Center of Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xiulun Gan
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xueqin Yang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Ling Zhou
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Jie Chen
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Yinjia He
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Rong Zhang
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Bixiu Zhu
- Department of Nephrology, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, China
| | - Lanying Liu
- Department of Nephrology, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, China
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Wan J, Ding Y, Nan S, Zhang Q, Sun J, Suo C, Ding M. Thymosin Beta 4 Is Involved in the Development of Electroacupuncture Tolerance. Front Cell Neurosci 2019; 13:75. [PMID: 30971892 PMCID: PMC6444270 DOI: 10.3389/fncel.2019.00075] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 02/14/2019] [Indexed: 12/28/2022] Open
Abstract
Background: Electroacupuncture (EA) tolerance, a negative therapeutic effect, is a gradual decline in antinociception because of its repeated or prolonged use. This study aims to explore the role of thymosin beta 4 (Tβ4), having neuro-protection properties, in EA tolerance (EAT). Methods: Rats were treated with EA once daily for eight consecutive days to establish EAT, effect of Tβ4 on the development of EAT was determined through microinjection of Tβ4 antibody and siRNA into the cerebroventricle. The mRNA and protein expression profiles of Tβ4, opioid peptides (enkephalin, dynorphin and endorphin), and anti-opioid peptides (cholecystokinin octapeptide, CCK-8 and orphanin FQ, OFQ), and mu opioid receptor (MOR) and CCK B receptor (CCKBR) in the brain areas (hypothalamus, thalamus, cortex, midbrain and medulla) were characterized after Tβ4 siRNA was administered. Results: Tβ4 levels were increased at day 1, 4, and 8 and negatively correlated with the changes of tail flick latency in all areas. Tβ4 antibody and siRNA postponed EAT. Tβ4 siRNA caused decreased Tβ4 levels in all areas, which resulted in increased enkephalin, dynorphin, endorphin and MOR levels in most measured areas during repeated EA, but unchanged OFQ, CCK-8, and CCKBR levels in most measured areas. Tβ4 levels were negatively correlated with enkephalin, dynorphin, endorphin, or MOR levels in all areas except medulla, while positively correlated with OFQ and CCK-8 levels in some areas. Conclusion: These results confirmed Tβ4 facilitates EAT probably through negatively changing endogenous opioid peptides and their receptors and positively influencing anti-opioid peptides in the central nervous system.
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Affiliation(s)
- Juan Wan
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Yi Ding
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Sha Nan
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Qiulin Zhang
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Jinrui Sun
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Chuanguang Suo
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Mingxing Ding
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
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Wan J, Qiu Z, Ding Y, Nan S, Ding M. The Expressing Patterns of Opioid Peptides, Anti-opioid Peptides and Their Receptors in the Central Nervous System Are Involved in Electroacupuncture Tolerance in Goats. Front Neurosci 2018; 12:902. [PMID: 30618545 PMCID: PMC6300483 DOI: 10.3389/fnins.2018.00902] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 11/19/2018] [Indexed: 12/24/2022] Open
Abstract
To investigate dynamic processes of enkephalin (ENK), cholecystokinin octapeptide (CCK-8), orphanin FQ (OFQ) and their receptors (μ opioid receptor, MOR; CCK B type receptor, CCKBR and opioid receptor-like 1 receptor, OPRL1) in the central nerve system (CNS) during electroacupuncture (EA) tolerance, EA of Sixty Hz was used to stimulate goats for 6 h. Pain threshold was measured using potassium iontophoresis. The expression levels of ENK, CCK-8, and OFQ and their receptors were determined with ELISA and qPCR, respectively. The results showed that the change rates of pain threshold in EA-treated goats decreased from 89.9 ± 11.7% at 0.5 h to –11.4 ± 8.9% at 6 h. EA induced the decreased ENK and increased CCK-8 and OFQ in the most measured nuclei. EA caused decreased preproenkephalin mRNAs in ACB, CAU, PVH, and PAG at 4 h, and decreased or unchanged MOR mRNAs at 2–6 h, but increased CCK mRNAs in CAU, PVT, PVH, PAG, and SCD at 4–12 h. Increased prepronociceptin mRNAs and fluctuated CCKBR and OPLR1 mRNAs were found in the most measured nuclei. ENK levels were positively correlated (p < 0.01) with the change rates of pain thresholds in the measured nuclei or areas while CCK-8 levels (or OFQ levels) were negatively correlated (p < 0.01) with the pain thresholds in CAU (or CAU and ACB). These results suggest that the development and recovery of EA tolerance may be associated with the specific expression patterns of opioid peptides, anti-opioid peptides and their receptors in the analgesia-related nuclei or areas.
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Affiliation(s)
- Juan Wan
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Zhengying Qiu
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.,Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Sciences (CAAS), Lanzhou, China
| | - Yi Ding
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Sha Nan
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Mingxing Ding
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
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Lioe-Ting O, Xiao-Hong C, van Ree J, Ji-Sheng H. Potentiation of Electroacupuncture-Induced Analgesia by Cck-B Antagonist L-365, 260 in Wistar Rats but Not in Acoustically-Evoked Epileptic Rats. Acupunct Med 2018. [DOI: 10.1136/aim.10.2.47] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Cholecystokinin octapeptide (CCK-8) is a neuropeptide with potent anti-opioid activity, which can antagonize morphine analgesia at nanogram dosage through activation of the CCK-B receptor in the central nervous system (CNS) of the rat. In the present study the CCK-B antagonist L-365,260 was injected intracerebroventricularly (icv) to Wistar rats to see its effect on the analgesia induced by electroacupuncture (EA) stimulation. A marked potentiation of EA-induced analgesia was observed. This potentiation was more prominent when EA of higher frequency was used, showing a rank order of 100Hz > 15Hz = 2/15Hz ≫ 2Hz. In a strain of rat with acoustically-evoked epileptic seizures (P77PMC rats), an extraordinarily strong analgesic effect was observed when EA of 100Hz was used; an effect similar to that in Wistar rats pre-treated with L-365,260. However, icv injected L-365,260 did not potentiate the analgesic effect induced by EA of any frequency in P77PMC rats. The results suggest that high frequency EA is more likely to increase the release of CCK-8 in the CNS as compared to low frequency EA; and also that P77PMC rats may have a functional deficit of the central CCK system probably due to a reduced rate of release of CCK-8 in the CNS, following EA stimulation.
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Affiliation(s)
- Oei Lioe-Ting
- Rudolf Magnus Inst. for Pharmacology, Utrecht University, Netherlands
| | | | - Jan van Ree
- Rudolf Magnus Inst. for Pharmacology, Utrecht University, Netherlands
| | - Han Ji-Sheng
- Dept. of Physiology, Beijing Medical University, China
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Yang Y, Li Q, He QH, Han JS, Su L, Wan Y. Heteromerization of μ-opioid receptor and cholecystokinin B receptor through the third transmembrane domain of the μ-opioid receptor contributes to the anti-opioid effects of cholecystokinin octapeptide. Exp Mol Med 2018; 50:1-16. [PMID: 29780163 PMCID: PMC5960647 DOI: 10.1038/s12276-018-0090-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Revised: 01/21/2018] [Accepted: 03/06/2018] [Indexed: 11/08/2022] Open
Abstract
Activation of the cholecystokinin type B receptor (CCKBR) by cholecystokinin octapeptide (CCK-8) inhibits opioid analgesia. Chronic opiate treatment leads to an increase in the CCK-8 concentration and thus enhances the antagonism of CCK-8 against opioid analgesia; the underlying molecular mechanisms remain of great interest. In the present study, we validated the colocalization of the μ-opioid receptor (MOR) and CCKBR in pain signal transmission-related spinal cord dorsal horn and dorsal root ganglion neurons of rats. Co-immunoprecipitation (Co-IP) and fluorescence lifetime-imaging-microscopy-based fluorescence resonance energy transfer (FLIM-FRET) assays showed that MOR heteromerized with CCKBR directly in transfected HEK293 cells. Combined with MOR mutant construction, the third transmembrane domain of MOR (TM3MOR) was demonstrated to participate in heteromerization with CCKBR. Receptor ligand binding, ERK phosphorylation and cAMP assays showed that MOR heteromerization with CCKBR weakened the activity of MOR. A cell-penetrating interfering peptide consisting of TM3MOR and TAT (a transactivator of HIV-1) sequences from the N terminal to the C terminal disrupted the MOR-CCKBR interaction and restored the activity of MOR in transfected HEK293 cells. Furthermore, intrathecal application of the TM3MOR-TAT peptide alleviated CCK-8-injection-induced antagonism to morphine analgesia in rats. These results suggest a new molecular mechanism for CCK-8 antagonism to opioid analgesia in terms of G-protein-coupled receptor (GPCR) interaction through direct heteromerization. Our study may provide a potential strategy for pain management with opioid analgesics.
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Affiliation(s)
- Yin Yang
- Neuroscience Research Institute, Peking University, Beijing, 100083, P. R. China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, 100083, P. R. China
| | - Qian Li
- Neuroscience Research Institute, Peking University, Beijing, 100083, P. R. China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, 100083, P. R. China
| | - Qi-Hua He
- Center of Medical and Health Analysis, Peking University, Beijing, 100083, P. R. China
| | - Ji-Sheng Han
- Neuroscience Research Institute, Peking University, Beijing, 100083, P. R. China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, 100083, P. R. China
- Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, 100083, P. R. China
| | - Li Su
- Center of Medical and Health Analysis, Peking University, Beijing, 100083, P. R. China.
| | - You Wan
- Neuroscience Research Institute, Peking University, Beijing, 100083, P. R. China.
- Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, 100083, P. R. China.
- Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, 100083, P. R. China.
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Hao L, Wen D, Gou H, Yu F, Cong B, Ma C. Over-expression of CCK1 Receptor Reverse Morphine Dependence. Int J Pept Res Ther 2018; 24:471-477. [PMID: 30147637 PMCID: PMC6096524 DOI: 10.1007/s10989-018-9696-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/19/2018] [Indexed: 12/30/2022]
Abstract
Studies demonstrated that cholecystokinin (CCK) system involved in morphine dependence and withdrawal. Our previous study showed that endogenous CCK system were up-regulated after chronic morphine exposure. Additionally, CCK1 receptor significantly blocked the inhibitory effect of exogenous CCK-8 on morphine dependence, but CCK2 receptor appears to be necessary for low concentrations of endogenous CCK to potentiate morphine dependence. Therefore, CCK1R and CCK2R function differently in chronic morphine dependence, but the mechanism is still unclear. In this study, HEK-293 cells co-transfected with µ-opioid receptors (HEK293-hMOR) and CCK1R or CCK2R were established. Cells were treated with 10 µM morphine for 6, 12, 16, 24 h and 100 µM naloxone precipitation for 15 min. cAMP overshoot was appeared at 12 h and was increased time dependently after morphine exposure in HEK293-hMOR cells. The cAMP overshoot did not appear in CCK1R-overexpressing HEK293-hMOR cells, while still appeared in CCK2R-overexpressing HEK293-hMOR cells. Over-expression of CCK1R reversed CREB and ERK1/2 activation in HEK293-hMOR cells exposed to morphine. Our study identifies over-expression of CCK1R significantly blocked morphine dependence, which was related with phosphorylation of CREB, and ERK1/2 signaling activation. While over-expression of CCK2R promoted morphine dependence, which was related with phosphorylation of CREB but not ERK1/2 signaling activation.
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Affiliation(s)
- Lijing Hao
- 1Department of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, 050017 Hebei Province People's Republic of China.,2Department of Anesthesiology, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, 050051 People's Republic of China
| | - Di Wen
- 1Department of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, 050017 Hebei Province People's Republic of China
| | - Hongyan Gou
- 1Department of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, 050017 Hebei Province People's Republic of China.,CUHK Shenzhen Research Institute, 2 Yuexing Road, Nanshan District, Shenzhen, 518057 People's Republic of China
| | - Feng Yu
- 1Department of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, 050017 Hebei Province People's Republic of China
| | - Bin Cong
- 1Department of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, 050017 Hebei Province People's Republic of China
| | - Chunling Ma
- 1Department of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, 050017 Hebei Province People's Republic of China
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Kim YK, Park JY, Kim SN, Yeom M, Lee S, Oh JY, Lee H, Chae Y, Hahm DH, Park HJ. What intrinsic factors influence responsiveness to acupuncture in pain?: a review of pre-clinical studies that used responder analysis. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 17:281. [PMID: 28545527 PMCID: PMC5445410 DOI: 10.1186/s12906-017-1792-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 05/15/2017] [Indexed: 01/26/2023]
Abstract
BACKGROUND Not many studies have investigated individual sensitivity to acupuncture. To explore the intrinsic factors related to individual responses to acupuncture, we reviewed published pre-clinical studies using responder analysis on pain. METHODS We searched the PubMed and EMBASE databases to June 2015. We included pre-clinical reports describing responders and non-responders to anti-nociceptive and analgesic effects of acupuncture in animal study. We identified the potential intrinsic factors which might be related with the response to acupuncture. RESULTS Totally, 216 potentially relevant articles were retrieved and 14 studies met our inclusion criteria. Rat (n = 1348) and rabbit (n = 56) were used, and only electroacupuncture (EA) was applied as an intervention. Results showed that high levels of cholecystokinin-8 and receptors were associated with poor responsiveness to EA. Endogenous opioids including β-endorphin and met-enkephalin, descending inhibitory norepinephrine and serotonin system, and hypothalamic 5'-AMP-activated protein kinase seemed to be associated with high-level responses. Spinal levels of neurotransmitters and pro-inflammatory cytokines were also differentially expressed depending on the EA sensitiveness. In the central nervous system, hypothalamus, periaqueductal grey, pituitary gland, and spinal cord were suggested to be involved in the EA responsiveness. Identified individual variations did not seem to be accidental, as the responsiveness to EA was replicated over time. However, methodological issues such as reproducibility, cut-off criteria, and clinical relevance need to be further elaborated. CONCLUSION Our study suggests that the identification of the biological factors differentiating responders from non-responders is necessary and it may aid in understanding how acupuncture modulates pain.
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Zhuang Y, Xing JJ, Li J, Zeng BY, Liang FR. History of acupuncture research. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2013; 111:1-23. [PMID: 24215915 DOI: 10.1016/b978-0-12-411545-3.00001-8] [Citation(s) in RCA: 125] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The acupuncture has been practiced in China for more than 3000 years and was spread to Europe and American from the sixteenth to the nineteenth century. The history of acupuncture research was initiated in the eighteenth century and developed rapidly since then. In the past, physicians tried hard to apply acupuncture into clinical practice, while scientists were focused on the possible characteristics of acupoints and meridians. In the modern time, scientists have strived hard to evaluate the real effectiveness of acupuncture and the underlying physiological and biological mechanisms of acupuncture. Reviewing research history from past to present, we are delighted to witness this wonderful development. Accumulated evidences that acupuncture is beneficial in various conditions significantly enhanced our understanding the mechanisms of acupuncture treatment. However, there is still no conclusive evidence in acupuncture clinical studies. The clinical research still needs great improving, while the basic research results need to be appropriately transformed into clinical outcomes. Based on current achievements, we believe that although the challenges and difficulties exist, a more collaborative, innovative, and integrated approach will help us to achieve further progress in future acupuncture research.
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Affiliation(s)
- Yi Zhuang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Patch clamp: a powerful technique for studying the mechanism of acupuncture. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:534219. [PMID: 23133497 PMCID: PMC3485550 DOI: 10.1155/2012/534219] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Accepted: 09/18/2012] [Indexed: 11/17/2022]
Abstract
Cellular and molecular events can be investigated using electrophysiological techniques. In particular, the patch-clamp method provides detailed information. In addition, the patch-clamp technique has become a powerful method for investigating the mechanisms underlying the effects of acupuncture. In this paper, recent researches on how acupuncture might modulate electrophysiological responses in the central nervous system (CNS) and affect peripheral structures are reviewed.
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A Tribute to Professor Ji-Sheng Han. Neurochem Res 2008; 33:1911-4. [DOI: 10.1007/s11064-008-9663-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2008] [Accepted: 03/11/2008] [Indexed: 10/22/2022]
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Shen J. Research on the neurophysiological mechanisms of acupuncture: review of selected studies and methodological issues. J Altern Complement Med 2002; 7 Suppl 1:S121-7. [PMID: 11822627 DOI: 10.1089/107555301753393896] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
This presentation reviews studies that contribute to an understanding of the neurophysiological mechanisms of acupuncture. A 1973 study, using volunteer medical students, looked into acupuncture's analgesic effect on experimentally induced pain and suggests that humoral factors may mediate acupuncture-induced analgesia. In a study of the possible role of the cerebrospinal fluid transmission of pain suppression effects of acupuncture, cerebrospinal fluid from acupuncture-treated rabbits was infused into recipient rabbits. The analgesic effect was observed in the recipient rabbits, suggesting that acupuncture-induced analgesia may be mediated by substances released in the cerebrospinal fluid. Studies of electroacupuncture in rats revealed that both low-frequency and high-frequency stimulation could induce analgesia, but that there are differential effects of low- and high-frequency acupuncture on the types of endorphins released. In another study, low-frequency electroacupuncture, given as median nerve stimulation in cats, was shown to protect the myocardium by inhibiting sympathetic pressor response and increasing myocardial oxygen demand. The development of neuroimaging tools, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), make noninvasive studies of acupuncture's effects on human brain activity possible. Studies using PET have shown that thalamic asymmetry present among patients suffering from chronic pain was reduced after the patients underwent acupuncture treatment. Other studies, using fMRI, have pointed to relationships between particular acupoints and visual-cortex activation. These powerful new tools open the possibility to new scientific studies of this ancient therapy.
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Affiliation(s)
- J Shen
- National Institutes of Health Clinical Center, Bethesda, Maryland 20892, USA
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17
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Abstract
This review focuses on the interaction of estrogen with the cholecystokinin (CCK) and endogenous opioid peptide systems in the medial preoptic nucleus, and how these interactions result in alterations of a stereotypic female reproductive behavior--lordosis. The medial preoptic nucleus is an integral part of a circuit controlling lordosis that extends from the limbic system through the hypothalamus. Estrogen alters the integration of sensory information in the circuit that results in the display of sexually receptive behavior. Estrogen determines the activity of CCK and endogenous opioid peptide systems through regulation of expression, release and interaction with specific receptors. Studies of each system individually have indicated that they are pivotal to the expression of lordosis. Recent studies demonstrate an estrogen-dependent interaction between endogenous opioid and CCK systems that control reproductive behavior.
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Affiliation(s)
- P Micevych
- Department of Neurobiology, Mental Retardation Research Center, UCLA School of Medicine, Box 951763, Los Angeles, CA 90095, USA.
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18
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Affiliation(s)
- D J Mayer
- Department of Anesthesiology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0695, USA.
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Han NL, Luo F, Bian ZP, Han JS. Synergistic effect of cholecystokinin octapeptide and angiotensin II in reversal of morphine induced analgesia in rats. Pain 2000; 85:465-469. [PMID: 10781920 DOI: 10.1016/s0304-3959(99)00294-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
The aim of this paper is to study the synergistic anti-analgesic effect of angiotensin II (Ang II) plus cholecystokinin octapeptide (CCK-8). Our previous studies have shown that both CCK-8 and Ang II are potent anti-opioid substances. Intracerebroventricular (i.c.v.) injection of CCK-8 or Ang II dose-dependently antagonizes morphine-induced analgesia (MIA). In the present study, we observed the combined effect of CCK-8 and Ang II in antagonizing MIA. CCK-8 and Ang II were injected intracerebroventricularly to rats in various proportions and doses. The results were analyzed with isobolographic analysis. Combined injection of CCK-8 and Ang II in a ratio of 1 ng: 2.5 microg or 1 ng: 5 microg produced significantly greater effect in antagonizing MIA. The ED(50) of the two ratios are only 18.5% and 27.5%, respectively, of the theoretical dose of simple addition. We conclude that CCK-8 and Ang II used in such dose ratios may antagonize MIA synergistically.
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Affiliation(s)
- Nian-Lin Han
- Neuroscience Research Institute, Beijing Medical University, Beijing 100083, PR China Department of Physiology, Yian-Bei Nursing School, Datong, Shanxi, PR China
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20
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Zhang X, de Araujo Lucas G, Elde R, Wiesenfeld-Hallin Z, Hökfelt T. Effect of morphine on cholecystokinin and mu-opioid receptor-like immunoreactivities in rat spinal dorsal horn neurons after peripheral axotomy and inflammation. Neuroscience 2000; 95:197-207. [PMID: 10619476 DOI: 10.1016/s0306-4522(99)00419-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
In order to further investigate the interaction between the octapeptide cholecystokinin and opioid analgesia in the spinal cord we used double-colour immunofluorescence to examine the anatomical distribution of cholecystokinin and mu-opioid receptors in the dorsal horn, as well as the effect of morphine on cholecystokinin- and mu-opioid receptor-like immunoreactivities following peripheral nerve injury and inflammation. Mu-opioid receptor-like immunoreactivity was present in 65.6% of cholecystokinin-positive neurons in laminae I and II of rat spinal cord. Conversely, 40.4% of mu-opioid receptor-positive neurons contained cholecystokinin-like immunoreactivity. Systemic application of morphine (1, 3 or 10 mg/kg; i.v.) after sciatic nerve section significantly, but reversibly, decreased mu-Opioid receptor-like immunoreactivity in the medial half of lamina II in segment L5 of the ipsilateral dorsal horn, and cholecystokinin-like immunoreactivity was also markedly reduced in the same region. These effects were dose- and time-dependent and could be prevented by naloxone preadministration. In contrast, no significant change in the pattern of distribution or intensity of mu-opioid receptor- and cholecystokinin-like immunoreactivities was observed in intact rats or during peripheral inflammation. These results provide a cellular basis for the interaction of mu-opioid receptors and cholecystokinin at the spinal level by showing a high degree of co-existence of these two molecules in local interneurons, and also show that morphine can induce rapid and short lasting effects on mu-opioid receptors after peripheral nerve injury. The results contribute to our understanding of how endogenous cholecystokinin reduces the analgesic effect of morphine.
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Affiliation(s)
- X Zhang
- Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
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21
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Gustafsson H, Afrah A, Brodin E, Stiller CO. Pharmacological characterization of morphine-induced in vivo release of cholecystokinin in rat dorsal horn: effects of ion channel blockers. J Neurochem 1999; 73:1145-54. [PMID: 10461906 DOI: 10.1046/j.1471-4159.1999.0731145.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Previous studies indicate that an increased release of cholecystokinin (CCK) in response to morphine administration may counteract opioid-induced analgesia at the spinal level. In the present study we used in vivo microdialysis to demonstrate that systemic administration of antinociceptive doses of morphine (1-5 mg/kg, s.c.) induces a dose-dependent and naloxone-reversible release of CCK-like immunoreactivity (CCK-LI) in the dorsal horn of the spinal cord. A similar response could also be observed following perfusion of the dialysis probe for 60 min with 100 microM but not with 1 microM morphine. The CCK-LI release induced by morphine (5 mg/kg, s.c.) was found to be calcium-dependent and tetrodotoxin-sensitive (1 microM in the perfusion medium). Topical application of either the L-type calcium channel blocker verapamil (50 microg) or the N-type calcium channel blocker omega-conotoxin GVIA (0.4 microg) onto the dorsal spinal cord completely prevented the CCK-LI release induced by morphine (5 mg/kg, s.c.). Our data indicate that activation of L- and N-type calcium channels is of importance for morphine-induced CCK release, even though the precise site of action of morphine in the dorsal horn remains unclear. The present findings also suggest a mechanism for the potentiation of opioid analgesia by L- and N-type calcium channel blocking agents.
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Affiliation(s)
- H Gustafsson
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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22
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Lucas GA, Hoffmann O, Alster P, Wiesenfeld-Hallin Z. Extracellular cholecystokinin levels in the rat spinal cord following chronic morphine exposure: an in vivo microdialysis study. Brain Res 1999; 821:79-86. [PMID: 10064790 DOI: 10.1016/s0006-8993(99)01068-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Conflicting results concerning the issue of whether or not chronic morphine exposure induces an increase in CCK biosynthesis have been found in many CNS sites, including the spinal cord, where CCK activity may contribute to the facilitation of the development of opiate tolerance. The present study was undertaken in order to monitor the extracellular level of CCK under spontaneous and stimulus-evoked release in the spinal cord dorsal horn of drug naive and morphine tolerant rats. Tolerance was induced by implantation of two morphine pellets (2x75 mg) which induced a stable morphine plasma concentration after 48 h post-implantation. The tail-flick test and naloxone precipitated withdrawal were used as indexes of tolerance and dependence to morphine. The effect of morphine-pellet implantation on basal and K+-induced release of CCK-like immunoreactivity (CCK-LI) in the rat dorsal horn were monitored with in vivo microdialysis 96 h after implantation of morphine or placebo pellets, when rats showed tolerance and dependence. Basal CCK levels were below the detection limit of the assay (0.6 pM) in both tolerant and normal animals. K+ (100 mM) in the perfusion medium induced a more than 3-fold increase of the extracellular level of CCK-LI in control animals, and a more than 4-fold increase on CCK-LI in morphine-pellet implanted animals. However, this difference was not significant. In addition, naloxone (2 mg/kg; i.v.), did not induce any change in the extracellular level of CCK in either group. The present study suggests that the modulatory interaction between CCK and opioids in the development of tolerance in the spinal cord may occur without necessarily increasing the extracellular level of CCK. Another possible explanation of the finding is that the microdialysis technique is not sensitive enough to detect differences in unstimulated CCK levels in normal and tolerant animals.
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Affiliation(s)
- G A Lucas
- Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Division of Clinical Neurophysiology, Huddinge University Hospital, S-141 86, Huddinge, Sweden
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23
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Xu MY, Lu HM, Wang SZ, Shi WY, Wang XC, Yang DX, Yang CX, Yang LZ. Effect of devazepide reversed antagonism of CCK-8 against morphine on electrical and mechanical activities of rat duodenum in vitro. World J Gastroenterol 1998; 4:524-526. [PMID: 11819361 PMCID: PMC4723444 DOI: 10.3748/wjg.v4.i6.524] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the antagonism of cholecystokinin octapeptide (CCK-8) against the effect of morphine and its mechanism.
METHODS: The method and mechanical activities of rat duodenum in vitro were recorded simultaneously.
RESULTS: Acetylcholine (ACh) could increase the amplitude and the number of the spike potential (SPA and SPN) of rat duodenum in vitro, followed by the increase of the duodenal contraction amplitudes (CA), showing a positive correlation. Morphine, on the contrary, inhibited the potentiation of ACh, showing a negative correlation. CCK-8 could antagonize the effects of morphine, i.e. the SPA and SPN were increased again, followed by the increase of CA. CCK-A receptor antagonist Devazepide could reverse the antagonism of CCK-8 to the effect of morphine.
CONCLUSION: CCK-8 could antagonize the effect of morphine which inhibited the potentiation of ACh on the duodenal activities in vitro. The antagonistic effect of CCK-8 on morphine was mainly mediated by CCK-A receptor.
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Chen XH, Geller EB, Adler MW. CCK(B) receptors in the periaqueductal grey are involved in electroacupuncture antinociception in the rat cold water tail-flick test. Neuropharmacology 1998; 37:751-7. [PMID: 9707289 DOI: 10.1016/s0028-3908(98)00028-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Cholecystokinin octapeptide (CCK-8) (0.25-2.0 ng), the CCK(A) receptor antagonist L-364,718 (60-100 ng) or the CCK(B) receptor antagonist L-365,260 (0.3125-1.25 ng) was administered into the periaqueductal grey (PAG) of male SD rats. The antinociceptive effect induced by electroacupuncture (EA) stimulation of different frequencies was then measured by the cold water tail-flick (CWT) test. The results showed that (1) microinjection of CCK-8 into the PAG can significantly block the antinociceptive effect induced by all frequencies of EA stimulation. The effectiveness of the blockade was 100 > 2 Hz. In addition, CCK-8 blocks the antinociception seen following termination of the electrical stimulation at 100 Hz; (2) microinjection of L-365,260 (1.25 ng) into the PAG significantly increased the 100 Hz EA antinociceptive effect but not the 2 Hz EA antinociceptive effect and microinjection of L-364,718 into PAG did not affect either 2 or 100 Hz EA antinociception. These results demonstrate that CCK-8 in the PAG can antagonize the antinociceptive effect induced by EA stimulation, and the CCK effect is likely to be mediated by the CCK(B) receptor, but not the CCK(A) receptor.
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Affiliation(s)
- X H Chen
- Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
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25
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Gustafsson H, de Araújo Lucas G, Schött E, Stiller CO, Alster P, Wiesenfeld-Hallin Z, Brodin E. Peripheral axotomy influences the in vivo release of cholecystokinin in the spinal cord dorsal horn-possible involvement of cholecystokinin-B receptors. Brain Res 1998; 790:141-50. [PMID: 9593865 DOI: 10.1016/s0006-8993(98)00060-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
An increased expression of cholecystokinin (CCK) messenger RNA (mRNA) as well as CCK-B receptor mRNA in dorsal root ganglion (DRG) cells following peripheral axotomy has previously been demonstrated. In the present in vivo microdialysis study, the effect of unilateral sciatic nerve section on basal and potassium-induced release of CCK-like (CCK-LI) immunoreactivity in the rat dorsal horn was investigated. We also compared the effects of the CCK-B receptor antagonist CI988 on basal and potassium-stimulated CCK-LI release in intact animals and in chronically axotomized rats. Perfusion of the microdialysis probe with KCl (100 mM) induced a more than 6-fold increase of the extracellular level of CCK-LI in control animals. In contrast, following unilateral sciatic nerve section the same KCl stimulation failed to evoke a release of CCK-LI ipsilaterally. However, after systemic administration of CI988 (1 mg kg-1, i.v.), 100 mM KCl induced a significant increase of the extracellular CCK-LI level in axotomized rats, similar to that observed in control animals. In control animals no effect of CI988 on KCl-stimulated CCK-LI release could be detected. CI988 by itself had no influence on the extracellular CCK-LI level in either nerve injured or control animals. The present data suggest that axotomy reduces the release of CCK-like immunoreactivity in the spinal cord by a mechanism involving the CCK-B receptor binding site.
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Affiliation(s)
- H Gustafsson
- Karolinska Institute, Department of Physiology and Pharmacology, Division of Pharmacological Pain Research, S-171 77 Stockholm, Sweden
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26
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Bossut D. Neuropeptides and Acupuncture: Coincidence or Specificity? J Altern Complement Med 1997. [DOI: 10.1089/acm.1997.3.s-109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Daniel Bossut
- Department of Neurology, Duke University, Durham, North Carolina
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27
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Micevych PE, Eckersell CB, Brecha N, Holland KL. Estrogen modulation of opioid and cholecystokinin systems in the limbic-hypothalamic circuit. Brain Res Bull 1997; 44:335-43. [PMID: 9370197 DOI: 10.1016/s0361-9230(97)00212-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The display of lordosis behavior has been correlated with the estrogen-induced expression of cholecystokinin (CCK) and enkephalin within the limbic-hypothalamic circuit. These neuropeptides have opposing effects on lordosis; for example, in the medial preoptic nucleus, CCK facilitates and opiates inhibit lordosis. Antisense oligodeoxynucleotide blockade of receptor expression indicated that CCK modulates lordosis in the medial preoptic nucleus through the CCK(A)-receptor. Sequence-specific antibodies directed against delta- and mu-opiate receptor proteins labeled fibers in the medial preoptic nucleus. Estrogen treatment of ovariectomized rats or etorphine (a nonselective opiate agonist) treatment altered the appearance of the immunoreactivity from a diffuse pattern to one of distinctly stained mu-opiate receptor immunoreactive cells and varicose fibers in the medial preoptic nucleus. Such a pattern of staining reflects an internalization of mu-opiate receptors following agonist stimulation. This type of internalization has been used as an indication of synaptic activity. The distribution of receptor internalization surrounds the distribution of CCK cells in the medial preoptic nucleus, suggesting that endogenous opioid peptides may modulate estrogen-induced CCK mRNA expression. Interestingly, nonselective and delta-opiate receptor selective antagonists potentiated the estrogen-induced CCK mRNA expression in the medial preoptic nucleus. Together, these results suggest that endogenous opioid peptides may modulate the estrogenic upregulation of CCK mRNA expression and demonstrate an important level of regulation of gene expression in which synaptic activity modifies hormonal input.
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Affiliation(s)
- P E Micevych
- Department of Neurobiology, Brain Research Institute, UCLA School of Medicine, Los Angeles, CA 90095, USA
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28
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Riley AL, Melton PM. Effects of mu- and delta-opioid-receptor antagonists on the stimulus properties of cholecystokinin. Pharmacol Biochem Behav 1997; 57:57-62. [PMID: 9164554 DOI: 10.1016/s0091-3057(96)00119-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Melton and Riley recently reported that the relatively selective mu-opioid-antagonist naloxone potentiated the stimulus properties of the gut peptide cholecystokinin (CCK). To assess whether such opioid potentiation is limited to activity at the mu-receptor subtype, in the present experiment the effects of the highly selective delta-antagonist naltrindole on CCK's stimulus properties were examined. Because in the initial report of naloxone's potentiation of CCK a relatively high, nonphysiologic dose of CCK (i.e., 13 micrograms/kg) was used as the training drug, in the current analysis subjects were trained to discriminate 5.6 micrograms/kg CCK from its vehicle and the assessments and comparisons of the effects of naloxone and naltrindole were based on this dose. Specifically, rats were administered 5.6 micrograms/kg CCK before saccharin-LiCl pairings and the CCK vehicle before saccharin alone. With such training, they rapidly acquired the drug discrimination, avoiding saccharin consumption when it was preceded by CCK and consuming the same saccharin solution when it was preceded by its vehicle. In subsequent generalization tests, doses of CCK that were ineffective in suppressing saccharin consumption (i.e., did not substitute for the training dose of CCK) did result in the suppression of saccharin consumption when combined with doses of the mu antagonist naloxone that alone had no effect on saccharin intake. On the other hand, the highly selective delta-opioid-receptor antagonist naltrindole was ineffective in potentiating the effects of CCK. Specifically, when naltrindole was combined with ineffective doses of CCK, subjects drank at control levels. The ability of naloxone to potentiate CCK's stimulus effects is consistent with a range of other demonstrations of the role of the mu-opioid-receptor subtype in CCK-opioid interactions, although the specific basis for the interaction remains unknown. Given recent findings on the effects of delta agonists and antagonists on CCK-induced activity, the failure of naltrindole to potentiate CCK's stimulus effects may be due to the absence of delta activity within this preparation, rather than the absence of delta mediation of CCK-opioid interactions in general.
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Affiliation(s)
- A L Riley
- Department of Psychology, American University, Washington, DC 20016, USA
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29
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Zhang LX, Li XL, Smith MA, Post RM, Han JS. Lipofectin-facilitated transfer of cholecystokinin gene corrects behavioral abnormalities of rats with audiogenic seizures. Neuroscience 1997; 77:15-22. [PMID: 9044370 DOI: 10.1016/s0306-4522(96)00420-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
To evaluate the potential for lipofectin-mediated central nervous system gene transfer, the plasmid coding for cholecystokinin was administered intracerebroventricularly to rats, which have congenital audiogenic seizures and high responses to peripheral electric stimulation-induced analgesia. Previous studies had shown that low brain cholecystokinin levels may be the neurochemical variable of rat's audiogenic seizure and high responses to the analgesia because cholecystokinin is an anticonvulsant and anti-opioid neuropeptide. Gene transfer of cholecystokinin corrected the increased susceptibility to audiogenic seizures and the high responses to analgesia for about one week. Similar administration of plasmid expressing beta-galactosidase indicated that the vector mainly transfected ependymal cells lining the ventricle and pia mater cells. The increased cholecystokinin messenger RNA and immunoreactivity in the hippocampus following stereotactic intrahippocampal administration of cholecystokinin plasmid was also demonstrated with in situ hybridization and immunohistochemistry techniques. These results suggest that lipofectin-mediated gene transfer will be useful for studies of brain function, the modification of behavior and gene therapy for central nervous system disorders.
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Affiliation(s)
- L X Zhang
- Neuroscience Research Center, Beijing Medical University, P. R. China
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30
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Liu NJ, Bao H, Li N, Yu YX, Han JS. Cholecystokinin octapeptide reverses the inhibitory effect induced by electroacupuncture on C-fiber evoked discharges. Int J Neurosci 1996; 86:241-7. [PMID: 8884394 DOI: 10.3109/00207459608986714] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Extracellular single unit recordings were made from spinal dorsal horn wide dynamic range neurons in spinal transected, urethane-anesthetized rats. The unit discharges elicited by noxious electrical stimulation of the hind paw were suppressed by electroacupuncture (15 Hz, 0.3 ms, 3 mA, 30 min) placed at the hind leg points (S-36 and SP-6). Local spinal superfusion with naloxone (20 micrograms/15 microliters) or CCK-8 (10 ng/15 microliters) attenuated, whereas CCK-B receptor antagonist L365,260 (2.5 micrograms/15 microliters) enhanced the electroacupuncture effect. These findings provide further evidence for the notion that CCK-8, in the spinal cord, functions as an antiopioid substrate that antagonizes opioid- or electroacupuncture-induced analgesia.
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Affiliation(s)
- N J Liu
- Neuroscience Research Center, Beijing Medical University, People's Republic of China
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31
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Wiesenfeld-Hallin Z, Xu XJ. The role of cholecystokinin in nociception, neuropathic pain and opiate tolerance. REGULATORY PEPTIDES 1996; 65:23-8. [PMID: 8876032 DOI: 10.1016/0167-0115(96)00068-7] [Citation(s) in RCA: 74] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- Z Wiesenfeld-Hallin
- Karolinska Institute, Department of Medical Laboratory Sciences and Technology, Huddinge University Hospital, Sweden
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32
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Zhang LX, Smith MA, Kim SY, Rosen JB, Weiss SR, Post RM. Changes in cholecystokinin mRNA expression after amygdala kindled seizures: an in situ hybridization study. BRAIN RESEARCH. MOLECULAR BRAIN RESEARCH 1996; 35:278-84. [PMID: 8717364 DOI: 10.1016/0169-328x(95)00230-p] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Cholecystokinin (CCK) can be a potent anticonvulsant neuropeptide in certain seizure models. Therefore, we examined whether seizures produced by electrical kindling of the amygdala or electroconvulsive seizures (ECS) would affect the expression of CCK mRNA in rat brain. Following a single kindled seizure, CCK mRNA expression was decreased about 20-58% in the amygdala. In contrast, after multiple consecutive kindled seizures, CCK mRNA expression was increased in the amygdala, cerebral cortex, CA1 pyramidal cell layer of the hippocampus and dentate hilus. A single ECS produced no effect on CCK mRNA expression, but multiple ECS increased expression in the interneurons of the hippocampus 24 h after the last seizure. Since seizures produced by ECS can be anticonvulsant to further ECS or kindled seizures, the CCK increases in the hippocampus may represent a compensatory anticonvulsant adaptation observed in both models. Overall, the kindling-induced alterations in CCK expression appear to be more complex involving multiple brain regions and distinct temporal properties.
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Affiliation(s)
- L X Zhang
- Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892, USA
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Abstract
The numerous endogenous opioid peptides (beta-endorphin, enkephalins, dynorphins ... ) and the exogenous opioids (such as morphine) exert their effects through the activation of receptors belonging to four main types, mu, delta, kappa and epsilon. Opioidergic neurones and opioid receptors are largely distributed centrally and peripherally. It is thus not surprising that opioids have numerous pharmacological effects and that endogenous opioids are thought to be involved in the physiological control of various functions, among which nociception is particularly emphasized. Some opioid targets may be components of homeostatic systems tending to reduce the effects of opioids. "Anti-opioid" properties have been attributed to various peptides, especially cholecystokinin (CCK), neuropeptide FF (NPFF) and melanocyte inhibiting factor (MIF)-related peptides. In addition, a particular place should be attributed, paradoxically, to opioid peptides themselves among the anti-opioid peptides. These peptides can oppose some of the acute effects of opioids, and a hyperactivation of anti-opioid peptidergic neurones due to the chronic administration of opioids may be involved in the development of opioid tolerance and/or dependence. In fact, CCK, NPFF and the MIF family of peptides have complex properties and can act as opioid-like as well as anti-opioid peptides. Thus, "opioid modulating peptides" would be a better term to designate these peptides, which probably participate, together with the opioid systems, in multiple feed-back loops for the maintenance of homeostasis. "Opioid modulating peptides" have generally been shown to act through the activation of their own receptors. For example, CCK appears to exert its anti-opioid actions mainly through the activation of CCK-B receptors, whereas its opioid-like effects seem to result from the stimulation of CCK-A receptors. However, the partial agonistic properties at opioid receptors of some MIF-related peptides very likely contribute to their ability to modulate the effects of opioids. CCK- and NPFF-related drugs have potential therapeutic interest as adjuncts to opioids for alleviating pain and/or for the treatment of opioid abuse.
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Chapman V, Honoré P, Buritova J, Besson JM. Cholecystokinin B receptor antagonism enhances the ability of a low dose of morphine to reduce c-Fos expression in the spinal cord of the rat. Neuroscience 1995; 67:731-9. [PMID: 7675199 DOI: 10.1016/0306-4522(95)00085-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Three hours after intraplantar carrageenin (6 mg/150 microliters) Fos-like immunoreactivity was predominantly observed in the superficial and deep laminae of the L4-L5 segments of the dorsal horn of the spinal cord in the rat. The total number of Fos-like immunoreactive neurons was equally divided between the superficial (laminae I-II) and deep laminae (laminae V-VI), 99 +/- 3 and 102 +/- 7 Fos-like immunoreactive neurons per section, respectively. In the absence of carrageenin stimulation a negligible number of Fos-like immunoreactive neurons were observed. Pre-administered systemic morphine (0.3 mg/kg) did not significantly influence the total number of Fos-like immunoreactive neurons 3 h after carrageenin. However, pre-administration of a higher dose of morphine (3 mg/kg) significantly reduced the total number of Fos-like immunoreactive neurons (28 +/- 8% reduction, P < 0.001, as compared with control carrageenin Fos-like immunoreactive expression), with this effect being equally divided between the superficial and deep laminae (29 +/- 5 and 29 +/- 6% reduction, respectively, P < 0.001, as compared with control carrageenin Fos-like immunoreactive expression, for both). Pre-administration of the selective cholecystokinin B receptor antagonist, L-365-260 (0.2 mg/kg), alone did not influence the total number of Fos-like immunoreactive neurons 3 h after carrageenin.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- V Chapman
- Physiopharmacologie du Système Nerveux, INSERM U.161, Paris, France
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35
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Han JS. Cholecystokinin octapeptide (CCK-8): a negative feedback control mechanism for opioid analgesia. PROGRESS IN BRAIN RESEARCH 1995; 105:263-71. [PMID: 7568886 DOI: 10.1016/s0079-6123(08)63303-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- J S Han
- Neuroscience Research Center, Beijing Medical University, China
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36
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Pu SF, Zhuang HX, Han JS. Cholecystokinin octapeptide (CCK-8) antagonizes morphine analgesia in nucleus accumbens of the rat via the CCK-B receptor. Brain Res 1994; 657:159-64. [PMID: 7820614 DOI: 10.1016/0006-8993(94)90963-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The analgesic effect of systemic morphine (4 mg/kg, s.c.) was antagonized in a dose-dependent manner by cholecystokinin octapeptide (CCK-8) (0.1-0.5 ng) administered bilaterally to the nucleus accumbens of the rat. This effect of CCK-8 could be reversed by devazepide, a CCK-A receptor antagonist, at 50 ng and 200 ng and by L-365,260, a CCK-B receptor antagonist, at 5 ng administered bilaterally to the nucleus accumbens. A marked potentiation of morphine analgesia was achieved by intra-nucleus accumbens injection of 200 ng devazepide or 5 ng L-365,260. Since the effect of L-365,260 in antagonizing the anti-opioid effect of CCK-8 in the nucleus accumbens is 40 times more potent than devazepide, it is suggested that the anti-opioid effect of CCK-8 is mediated by CCK-B receptors. In conclusion, nucleus accumbens is a strategic site where CCK-8 exerts an anti-opioid activity, most probably via the CCK-B receptors.
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Affiliation(s)
- S F Pu
- Neuroscience Research Center, Beijing Medical University, People's Republic of China
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37
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Pu S, Zhuang H, Lu Z, Wu X, Han J. Cholecystokinin gene expression in rat amygdaloid neurons: normal distribution and effect of morphine tolerance. BRAIN RESEARCH. MOLECULAR BRAIN RESEARCH 1994; 21:183-9. [PMID: 8170343 DOI: 10.1016/0169-328x(94)90249-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Previous studies have shown that repeated opioid administration induces a tolerance to opioid, presumably due in part to an opioid-mediated compensatory increase in brain cholecystokinin (CCK) synthesis and/or release. In this study, in situ hybridization histochemistry was used to examine the effect of morphine tolerance on CCK gene expression in the amygdala of rat brains, by using a 35S-labeled synthetic oligonucleotide probe. CCK mRNA-positive neurons in normal rats were seen throughout the amygdaloid complex, with the most heavily labeled neurons in lateral, basal, and cortical nuclei, followed by the medial nucleus. Only a few labeled neurons were found in central and intercalated nuclei. The development of morphine tolerance in the rat was associated with increased hybridization signals for CCK mRNA in each subnucleus of the amygdala. Increases were seen in the numbers of positively labeled neurons and/or the numbers of hybridization grains per positively labeled neuron. Furthermore, differential patterns of increase in CCK mRNA in morphine tolerant rats occurred in different subnuclei of the amygdala, with the highest magnitude of increase in the cortical nucleus, followed in order by the medial, central, basal, intercalated and lateral nuclei. The present study demonstrated that repeated administration of morphine increased CCK gene expression in the amygdaloid complex, and suggested that the development of the tolerance to morphine analgesia is due, in part, to an increase in CCK activity in the amygdaloid complex. These findings substantiate the hypothesis that long-term administration of opioid may induce a compensatory increase in CCK synthesis and/or release, which then results in a progressive antagonism of opioid analgesia.
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Affiliation(s)
- S Pu
- Department of Physiology, First School of Clinical Medicine, Beijing Medical University, People's Republic of China
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38
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Melton PM, Riley AL. An assessment of the interaction between cholecystokinin and the opiates within a drug discrimination procedure. Pharmacol Biochem Behav 1993; 46:237-42. [PMID: 8255917 DOI: 10.1016/0091-3057(93)90347-v] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Recently, cholecystokinin (CCK) has been reported to antagonize a variety of opiate-induced effects, including nociception, body shaking, thermoregulation, and locomotion. Consistent with these results, a number of CCK antagonists potentiate the opiates in a range of behavioral and physiological assessments. The present study further examined the interaction between CCK and the opiates within the conditioned taste aversion baseline of drug discrimination learning, a design that utilizes the stimulus properties of the drug to control consummatory behavior. Specifically, animals injected with CCK prior to saccharin-LiCl pairings and the CCK vehicle prior to saccharin alone rapidly acquired the CCK-vehicle discrimination, avoiding saccharin consumption following the administration of CCK and consuming the same saccharin solution following the vehicle. Although the stimulus properties of CCK did not generalize to either naloxone or diprenorphine, morphine blocked and naloxone potentiated CCK's stimulus effects. These data are thus consistent with a physiological (rather than a pharmacological) interaction between CCK and the opiates.
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Affiliation(s)
- P M Melton
- Department of Psychology, American University, Washington, DC 20016-8062
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39
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Bian JT, Sun MZ, Han JS. Reversal of electroacupuncture tolerance by CCK-8 antiserum: an electrophysiological study on pain-related neurons in nucleus parafascicularis of the rat. Int J Neurosci 1993; 72:15-29. [PMID: 8225797 DOI: 10.3109/00207459308991620] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Two varieties of neurons were found in nucleus parafascicularis (pf) of the rat: one responds to noxious stimuli with an increase in firing (pain-excited neuron, PEN), the other with a decrease in firing (pain-inhibited neuron, PIN). Electroacupuncture (EA) has been shown to suppress PEN and excite PIN, which can be taken as an electrophysiological index for EA analgesia. This effect of EA subsided after prolonged (6 h) EA stimulation, suggesting the development of tolerance to EA. Intracerebroventricular (icv) injection of CCK-8 antiserum aiming at neutralizing endogenously released CCK-8 resulted in a complete restoration of the EA effect. Normal rabbit serum was not effective. CCK-8 antiserum per se did not affect the firing pattern of the PEN or PIN in nontolerant rat. The results obtained from single neuron recording in anesthetized animals thus confirmed those obtained in intact animals using the tail flick as the end point, implying that an excess of endogenously released CCK-8 may constitute one of the mechanisms for the development of EA tolerance.
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Affiliation(s)
- J T Bian
- Department of Physiology, Beijing Medical University, PR China
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40
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Ma QP, Zhou Y, Han JS. Noxious stimulation accelerated the expression of c-fos protooncogene in cholecystokininergic and dopaminergic neurons in the ventral tegmental area. Peptides 1993; 14:561-6. [PMID: 8332552 DOI: 10.1016/0196-9781(93)90145-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Cholecystokininergic (CCK) and dopaminergic systems in the midbrain have been implicated in pain modulation. In the present study, Fos immunoreactivity was used as a marker of neuronal activity to investigate if subcutaneous injection of formalin (a model of noxious stimulation) could activate the CCKergic and dopaminergic neurons in the midbrain. Noxious stimulation increased significantly the numbers of Fos-positive CCKergic and dopaminergic neurons in the ventral tegmental area (VTA), whereas no significant changes in the numbers of Fos-positive CCKergic or dopaminergic neurons were observed in other midbrain nuclei. These results indicate that the VTA may play a role in pain modulation.
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Affiliation(s)
- Q P Ma
- Department of Physiology, Beijing Medical University, People's Republic of China
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41
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Zhou Y, Sun YH, Zhang ZW, Han JS. Increased release of immunoreactive cholecystokinin octapeptide by morphine and potentiation of mu-opioid analgesia by CCKB receptor antagonist L-365,260 in rat spinal cord. Eur J Pharmacol 1993; 234:147-54. [PMID: 8387008 DOI: 10.1016/0014-2999(93)90948-h] [Citation(s) in RCA: 86] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
This is the first report showing, in an in vivo study, that systemic morphine produced a marked (89%, P < 0.01) increase of the cholecystokinin octapeptide (CCK-8) immunoreactivity in the perfusate of the rat spinal cord, an effect completely reversed by naloxone. Since CCK-8 has been shown to possess potent anti-opioid activity at a spinal level, a blockade of the spinal cholecystokinin effect would be expected to potentiate opiate analgesia. With tail flick latency as a nociceptive index, it was found that intrathecal (i.t.) injection of a novel CCKB antagonist L-365,260 produced a marked potentiation of the analgesic effect induced by the mu-opioid agonists morphine (4 mg/kg s.c.) or ohmefentanyl (32 ng i.t.). Similar effects were obtained with the CCKA antagonist devazepide at a dose 40-50 times higher than that of L-365,260. Both devazepide and L-365,260 showed a bell-shaped dose-response curve. The results confirm the notion that an increased release of CCK-8 may constitute a self-limiting process for opioid effects at the spinal level, and that it is the CCKB receptor which mediates the anti-opioid effect of CCK-8 in the rat spinal cord.
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Affiliation(s)
- Y Zhou
- Neuroscience Research Center, Beijing Medical University, People's Republic of China
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42
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Zhou Y, Sun YH, Shen JM, Han JS. Increased release of immunoreactive CCK-8 by electroacupuncture and enhancement of electroacupuncture analgesia by CCK-B antagonist in rat spinal cord. Neuropeptides 1993; 24:139-44. [PMID: 8474632 DOI: 10.1016/0143-4179(93)90077-n] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cholecystokinin octapeptide (CCK-8) in CNS has been shown to function as a neuropeptide with potent anti-opioid activity. It hinders opioid analgesia and facilitates opioid tolerance. The present study showed that electroacupuncture (EA) stimulation produced a marked increase of the CCK-8 immunoreactivity (ir) in the perfusate of the rat spinal cord. The increase of CCK-8-ir was most marked in response to EA of 100 Hz and 15 Hz, and less marked in response to EA of 2 Hz. Since CCK-8 has been shown to possess potent anti-opioid activity at the spinal level, blockade of the spinal CCK effect would be expected to potentiate EA-induced analgesia which is known to be opioid-mediated. Intrathecal (i.t.) administration of CCK-B antagonist L-365,260 per se did not affect tail flick latency (TFL) to any significant extent, yet it potentiated EA induced analgesia in a dose- and frequency-dependent manner. The potentiation was most marked at a dose range of 2.5-5.0 ng (i.t.) and at a frequency rank order of 100 Hz > 15 Hz > 2 Hz. The results suggest that an increased release of CCK-8 following EA may limit the effect of opioid peptides, and that the CCK-B receptor mediates the anti-opioid effect of CCK-8 in rat spinal cord.
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Affiliation(s)
- Y Zhou
- Neuroscience Research Center, Beijing Medical University, People's Republic of China
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43
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Role of Cholecystokinin Type B Receptor in Nociception Studied with Peptide Agonists and Antagonists. ACTA ACUST UNITED AC 1993. [DOI: 10.1016/b978-0-12-185271-9.50014-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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44
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Wang J, Ren M, Han J. Mobilization of calcium from intracellular stores as one of the mechanisms underlying the antiopioid effect of cholecystokinin octapeptide. Peptides 1992; 13:947-51. [PMID: 1336191 DOI: 10.1016/0196-9781(92)90054-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
In enzymatically dissociated brain cells prepared from neonatal rats, KCl produced a significant increase in [Ca2+]i and this increase could be prevented by verapamil or nifedipine, known to block voltage-sensitive calcium channels. The opioid receptor agonists ohmefentanyl (OMF, mu agonist), [D-Pen2,D-Pen5]enkephalin (DPDPE, delta agonist), and 66A-078 (kappa agonist) produced a marked suppression of the Ca2+ influx induced by high K+ depolarization. The suppressive effect of OMF, DPDPE, and 66A-078 on the high K(+)-induced increase in [Ca2+]i was markedly reversed by their respective antagonists beta-funaltrexamine (beta-FNA), ICI174864, and nor-binaltorphimine (nor-BNI). Cholecystokinin octapeptide (CCK-8), at concentrations of 0.3, 3.0, and 30 nM, dose-dependently mobilized Ca2+ from intracellular stores. While CCK-8 30 nM did not affect significantly the increase of [Ca2+]i following high K+, it did reverse the suppression of the high K(+)-induced increase in [Ca2+]i by the mu agonist OMF and the kappa agonist 66A-078, but not that by the delta agonist DPDPE. The results suggested that while opioid ligands suppress [Ca2+]i by blocking voltage-operated Ca2+ influx, the antiopioid effect of CCK-8 seems to be operated via mobilization of Ca2+ from intracellular stores.
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Affiliation(s)
- J Wang
- Department of Physiology, Beijing Medical University, People's Republic of China
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45
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Xu XJ, Wiesenfeld-Hallin Z, Hughes J, Horwell DC, Hökfelt T. CI988, a selective antagonist of cholecystokininB receptors, prevents morphine tolerance in the rat. Br J Pharmacol 1992; 105:591-6. [PMID: 1628146 PMCID: PMC1908430 DOI: 10.1111/j.1476-5381.1992.tb09024.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
1. The effect of chronic treatment with CI988, a recently developed selective antagonist of cholecystokinin type-B receptors (CCKB receptors) on the tolerance to morphine analgesia was studied in rats with the hot plate test. 2. Morphine tolerance was induced with the use of two paradigms. Morphine was injected i.p. either in a schedule of increasing doses (1-32 mg kg-1) twice daily for 6 days or at a fixed dose (3 mg kg-1) daily for 29 days. 3. In both series of experiments, tolerance to the analgesic effect of morphine was prevented by simultaneous treatment with i.p. CI988. Chronic treatment with only CI988 daily for up to 29 days did not reduce the analgesic effect of a weekly injection of morphine. 4. CI988 did not diminish the physical dependence to morphine, as examined with naloxone precipitated withdrawal. 5. The present results provide evidence that chronic treatment with a selective CCKB receptor antagonist could prevent tolerance to the analgesic effect of morphine without affecting morphine-induced physical dependence. Application of CCK antagonists may be clinically important in treating chronic pain patients by preventing morphine tolerance and by eliminating the need to increase morphine doses to unacceptable levels.
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Affiliation(s)
- X J Xu
- Department of Clinical Physiology, Karolinska Institute, Huddinge University Hospital, Sweden
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46
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Hökfelt T, Cortés R, Schalling M, Ceccatelli S, Pelto-Huikko M, Persson H, Villar MJ. Distribution patterns of CCK and CCK mRNA in some neuronal and non-neuronal tissues. Neuropeptides 1991; 19 Suppl:31-43. [PMID: 1881531 DOI: 10.1016/0143-4179(91)90081-s] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Mutt and Jorpes (49) originally isolated cholecystokinin (CCK) from porcine intestine. Subsequently, it was recognized that CCK/gastrin-like material could be found in the rat brain (74), and it was later shown mainly to represent the C-terminal octapeptide (CCK-8) (2, 12-14, 48, 54, 55). These radioimmunoassay studies have been supplemented by numerous immunohistochemical investigations showing extensive CCK immunoreactive neuron systems in the brain and spinal cord (20, 26, 27, 31, 37, 40, 42, 44, 72, 75, 76). During recent years several groups have employed in situ hybridisation and radioactively labelled probes complementary to CCK mRNA and partly confirmed results from immunohistochemical studies but also revealed new interesting findings (3, 5, 6, 30, 41, 58, 64-66, 77). Several lines of evidence indicate that CCK-8 may act as a neurotransmitter or neuromodulator in many areas of the central nervous system. The development of new CCK antagonists has opened up new possibilities to understand the functional significance of CCK peptides in the neurons and other systems. The aim of the present article is to briefly review the distribution of some of the CCK systems and in this way define possible targets for these new types of drugs. Focus will be on cerebral cortex in view of the theme of the meeting, anxiety, on spinal cord as a basis for discussion of CCK and pain, and finally CCK/gastrin peptides in sperm will be discussed. The question of coexistence of CCK and dopamine in mesencephalic neurons is reviewed in a parallel article (28).
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Affiliation(s)
- T Hökfelt
- Department of Histology and Neurobiology, Karolinska Institutet, Stockholm, Sweden
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47
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Zaphiropoulos A, Charnay Y, Vallet P, Constantinidis J, Bouras C. Immunohistochemical distribution of corticotropin-like intermediate lobe peptide (CLIP) immunoreactivity in the human brain. Brain Res Bull 1991; 26:99-111. [PMID: 1849784 DOI: 10.1016/0361-9230(91)90194-o] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The immunocytochemical distribution of CLIP (corticotropin-like intermediate lobe peptide) or ACTH(18-39), a small biologically active peptide, was examined in the human brain, using a monoclonal antibody against this peptide. Groups of CLIP-immunoreactive cell bodies, small to medium size and bipolar or triangular in shape, were found in the basal hypothalamus extending from the retrochiasmatic region to the premammillary nuclei area. Immunoreactive fibers with varicosities, terminals and "pipe shape" structures, were distributed within the hypothalamus, limbic structures, the brainstem and spinal cord nuclei, forming a particularly rich network in the hypothalamus, the preoptic area, the septal region, the amygdala and the upper brainstem periaqueductal gray matter. The above neuroanatomical observations confirm and extend previous findings in animals, strengthening even more the possibility that this peptide may be involved in numerous behavioral, autonomic and physiological functions such as regulation of sleep-waking cycle, pain control and respiratory and cardiovascular regulation.
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48
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Wang XJ, Han JS. Modification by cholecystokinin octapeptide of the binding of mu-, delta-, and kappa-opioid receptors. J Neurochem 1990; 55:1379-82. [PMID: 2168937 DOI: 10.1111/j.1471-4159.1990.tb03149.x] [Citation(s) in RCA: 61] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Previous study has shown that cholecystokinin (CCK) octapeptide (CCK-8) suppressed the binding of opioid receptors to the universal opioid agonist [3H]etorphine. In the present study, highly selective tritium-labeled agonists for the mu-[(tryrosyl-3,5-3H][D-Ala2,MePhe4,Gly-ol5]enkephalin ([3H]DAGO], delta- ([tyrosyl-3,5-3H][D-Pen2,5]enkephalin ([3H]DPDPE], and kappa- ([3H]U69,593) opioid receptors were used to clarify which type(s) of opioid receptor in rat brain homogenates is suppressed by CCK-8. In the competition experiments, CCK-8 suppressed the binding of [3H]DAGO and [3H]U69,593 but not that of [3H]DPDPE to the respective opioid receptor. This effect was blocked by the CCK antagonist proglumide at 1 mumol/L. In the saturation experiments, CCK-8 at concentrations of 0.1 nmol/L to 1 mumol/L decreased the Bmax of [3H]DAGO binding sites without affecting the KD; on the other hand, CCK-8 increased the KD of [3H]U69,593 binding without changing the Bmax. The results suggest that CCK-8 inhibits the binding of mu- and kappa-opioid receptors via the activation of CCK receptors.
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MESH Headings
- Animals
- Brain/metabolism
- Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
- Enkephalin, D-Penicillamine (2,5)-
- Enkephalins/metabolism
- Etorphine/metabolism
- Kinetics
- Rats
- Rats, Inbred Strains
- Receptors, Opioid/drug effects
- Receptors, Opioid/metabolism
- Receptors, Opioid, delta
- Receptors, Opioid, kappa
- Receptors, Opioid, mu
- Sincalide/pharmacology
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Affiliation(s)
- X J Wang
- Department of Physiology, Beijing Medical University, People's Republic of China
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49
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Wiesenfeld-Hallin Z, Xu XJ, Hughes J, Horwell DC, Hökfelt T. PD134308, a selective antagonist of cholecystokinin type B receptor, enhances the analgesic effect of morphine and synergistically interacts with intrathecal galanin to depress spinal nociceptive reflexes. Proc Natl Acad Sci U S A 1990; 87:7105-9. [PMID: 1698290 PMCID: PMC54692 DOI: 10.1073/pnas.87.18.7105] [Citation(s) in RCA: 102] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The effects of systemic PD134308 [0.1-3 mg/kg; an antagonist of the cholecystokinin (CCK) type B receptor], morphine, and intrathecal (i.t.) galanin (GAL) on the excitability of the spinal nociceptive flexor reflex and in the hot plate test were examined in rats. PD134308 caused a weak naloxone-reversible depression of the flexor reflex and a moderate antinociceptive effect in the hot plate test. However, PD134308 significantly potentiated the antinociceptive effect of morphine as well as its depressive effect on the flexor reflex. PD134308 and i.t. GAL synergistically depressed the flexor reflex, an effect that was reversed by naloxone. Finally, the magnitude and duration of the depression of the flexor reflex by morphine were synergistically increased by coadministering PD134308 and GAL i.t. The results demonstrated that a CCK antagonist directed to the central CCK type B receptor potentiates the analgesic effects of opioids and nonopioid drugs at the spinal level, thus supporting the notion that CCK in the central nervous system may be an endogenous, physiological opioid antagonist.
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50
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Wang XJ, Wang XH, Han JS. Cholecystokinin octapeptide antagonized opioid analgesia mediated by mu- and kappa- but not delta-receptors in the spinal cord of the rat. Brain Res 1990; 523:5-10. [PMID: 1976419 DOI: 10.1016/0006-8993(90)91629-u] [Citation(s) in RCA: 57] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Intrathecal (ith) injection of cholecystokinin octapeptide (CCK-8) to the rat with single dose of 4 or 40 ng, or successive doses from 0.1 to 1 microgram at 10 min intervals produced neither analgesia nor hyperalgesia. However, the analgesia produced by ith injection of PL017, a specific mu-receptor agonist or 66A-078, a specific kappa-receptor agonist could be markedly antagonized by CCK-8 at a dose as small as 4 ng. In contrast, analgesia produced by ith injection of delta-agonist DPDPE could not be blocked by CCK-8 even at a dose as high as 40 ng. Since the effect of CCK-8 could be totally reversed by the CCK receptor antagonist proglumide, this effect is most probably mediated by CCK receptors.
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Affiliation(s)
- X J Wang
- Department of Physiology, Beijing Medical University, People's Republic of China
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