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Liu Z, Xu Y, Liu W, Wang L, Dong Z, Zeng J. Macleaya cordata protopine total alkaloids as potential treatment for diarrhoea: Mechanistic insights and target identification. Res Vet Sci 2025; 189:105633. [PMID: 40184723 DOI: 10.1016/j.rvsc.2025.105633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 02/25/2025] [Accepted: 03/28/2025] [Indexed: 04/07/2025]
Abstract
Diarrhoea remains a major public health concern, particularly affecting young children and livestock. Macleaya cordata protopine total alkaloids (MPTA), a standardized extract approved in China for poultry diarrhoea, has demonstrated anti-inflammatory properties in intestinal disorders. The study aims to investigate the antidiarrheal mechanism of MPTA using castor oil- and E. coli-induced diarrhoea models in mice. We first tested MPTA for acute oral toxicity. Subsequently, the effect of MPTA on castor oil- and E. coli-induced diarrhoea in mice based on LD50 results. Network pharmacology analysis and target competition assays (inhibitors and antagonists) were integrated to identify targets for MPTA's antidiarrheal effects. Molecular docking was used to verify the binding ability of MPTA components to these receptors. The LD50 of MPTA was determined to be 426.1 mg/kg. The optimal MPTA activity was found at 8 mg/kg in both castor oil and in infectious models. Network pharmacology analysis revealed potential targets and pathways of MPTA against intestinal motility. The impact of MPTA on cholinergic, serotonin, dopaminergic, and adrenergic receptors was assessed using standard inhibitors and agonists to induce intestinal smooth muscle contractions or relaxations. Molecular docking confirmed the binding ability of MPTA components to these receptors. In conclusion, MPTA exhibits significant antidiarrheal effects in both castor oil and E. coli-induced diarrhoea models. Its mechanism may involve modulation of cholinergic, serotonin, dopaminergic, and adrenergic receptors, as well as inhibition of ion channels and anti-inflammatory actions. These findings highlight the potential of MPTA as a novel therapeutic agent for diarrhoea.
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Affiliation(s)
- Zhiqin Liu
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; Hunan Province Key Laboratory of Traditional Chinese Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; Chinese Medicinal Materials Breeding Innovation Centre of Yuelushan Laboratory, Changsha 410128, China
| | - Yufeng Xu
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; Hunan Province Key Laboratory of Traditional Chinese Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; Chinese Medicinal Materials Breeding Innovation Centre of Yuelushan Laboratory, Changsha 410128, China
| | - Wei Liu
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; Hunan Province Key Laboratory of Traditional Chinese Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; Chinese Medicinal Materials Breeding Innovation Centre of Yuelushan Laboratory, Changsha 410128, China
| | - Lin Wang
- Hunan Province Key Laboratory of Traditional Chinese Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; Chinese Medicinal Materials Breeding Innovation Centre of Yuelushan Laboratory, Changsha 410128, China; College of Horticulture, Hunan Agricultural University, Changsha 410128, China
| | - Zhen Dong
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; Hunan Province Key Laboratory of Traditional Chinese Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; Chinese Medicinal Materials Breeding Innovation Centre of Yuelushan Laboratory, Changsha 410128, China.
| | - Jianguo Zeng
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; Hunan Province Key Laboratory of Traditional Chinese Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; Chinese Medicinal Materials Breeding Innovation Centre of Yuelushan Laboratory, Changsha 410128, China.
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Posa L, Romano G, Ji X, Khan S, Paz BM, Han GW, Nazarova AL, Zaidi SA, Ranjbar M, Pleil K, Katritch V, Gati C, Trauner D, Levitz J. An opioid efficacy switch for reversible optical control of peripheral analgesia. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.12.16.628735. [PMID: 39764058 PMCID: PMC11702541 DOI: 10.1101/2024.12.16.628735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2025]
Abstract
The mu-opioid receptor (MOR) is a major target for the treatment of pain. However, opioids are prone to side effects which limit their effectiveness as analgesics and can lead to opioid use disorders or, even, lethal overdose. The systemic administration of opioid agonists makes it both very difficult to decipher their underlying circuit mechanisms of action and to limit drug action to specific receptor subpopulations to isolate therapeutic effects from adverse side effects. Here we design, synthesize, and characterize a reversibly photoswitchable morphinan agonist termed "azo-morphine-3" ( AM-3 ) which interconverts from low to high efficacy in response to different wavelengths of light to enable optical control of MOR signaling. Cryo-EM structures of the low efficacy " trans " and high efficacy " cis " states of AM-3 bound to the MOR reveal distinct binding modes of the photoswitchable azobenzene moiety, each inducing unique structural dynamics, providing insight into the molecular basis of agonist efficacy. In mice, AM-3 drives reversible and repeatable optical control of anti-nociception with a reduced side effect profile owing to its restriction to the periphery and its ability to be locally activated at the site of pain.
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Wang X, Guo R, Yu Z, Zikela L, Li J, Li S, Han Q. Torreya grandis Kernel Oil Alleviates Loperamide-Induced Slow Transit Constipation via Up-Regulating the Colonic Expressions of Occludin/Claudin-1/ZO-1 and 5-HT3R/5-HT4R in BALB/c Mice. Mol Nutr Food Res 2024; 68:e2300615. [PMID: 38152983 DOI: 10.1002/mnfr.202300615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/11/2023] [Indexed: 12/29/2023]
Abstract
SCOPE Torreya grandis kernel has traditionally been used to remove intestinal parasites and increases intestinal motility. However, the effect of Torreya grandis kernel oil (TKO) on constipation has not yet been investigated. Therefore, mouse model is used to investigate the effect of TKO on slow transit constipation (STC) and its possible mechanism. METHODS AND RESULTS The effects of TKO on intestinal motility of STC mice are evaluated by fecal weight, fecal water content, colon length, defecation test, and intestinal propulsion test. The mechanism of TKO alleviating STC is explored by detecting biochemical analysis, histological analysis, western blot, qRT-PCR, immunohistochemistry, and gut microbiota analysis. The results reveal that TKO effectively promotes defecation and intestinal motility, increases the level of endothelin-1, and restores the histopathological morphology of the colon under LOP pretreatment. The expression levels of occludin, claudin-1, and zonula occludens-1 (ZO-1) mRNA and protein are up-regulated in mice receiving TKO treatment. The colonic 5-hydroxytryptamine 3R/4R (5-HT3R/5-HT4R) expressions are also increased by TKO supplementation. Additionally, TKO rescues LOP-caused disorders of the gut microbiota. CONCLUSION Consumption of TKO is beneficial to STC recovery, and it can alleviate LOP-induced STC by up-regulating the colonic expressions of Occludin/Claudin-1/ZO-1 and 5-HT3R/5-HT4R.
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Affiliation(s)
- Xuezhu Wang
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Rui Guo
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Zhuoli Yu
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Lalai Zikela
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Jiaomei Li
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Songtao Li
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Qiang Han
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
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Tuhin MTH, Liang D, Liu F, Aldawod H, Amin TU, Ho JS, Emara R, Patel AD, Felmlee MA, Park MS, Uchizono JA, Alhamadsheh MM. Peripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects. Nat Commun 2022; 13:3590. [PMID: 35739116 PMCID: PMC9226319 DOI: 10.1038/s41467-022-31342-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 06/14/2022] [Indexed: 11/09/2022] Open
Abstract
Several investigations into the sites of action of opioid analgesics have utilized peripherally acting mu-opioid receptor antagonists (PAMORAs), which have been incorrectly assumed to possess limited permeability across the blood-brain barrier. Unfortunately, the poor pharmacokinetic properties of current PAMORAs have resulted in misunderstandings of the role of central nervous system and gastrointestinal tract in precipitating side effects such as opioid-induced constipation. Here, we develop a drug delivery approach for restricting the passage of small molecules across the blood-brain barrier. This allows us to develop naloxone- and oxycodone-based conjugates that display superior potency, peripheral selectivity, pharmacokinetics, and efficacy in rats compared to other clinically used PAMORAs. These probes allow us to demonstrate that the mu-opioid receptors in the central nervous system have a fundamental role in precipitating opioid-induced constipation. Therefore, our conjugates have immediate use as pharmacological probes and potential therapeutic agents for treating constipation and other opioid-related side effects.
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Affiliation(s)
- Md Tariqul Haque Tuhin
- Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, 95211, US
| | - Dengpan Liang
- Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, 95211, US
| | - Fang Liu
- Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, 95211, US
| | - Hala Aldawod
- Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, 95211, US
| | - Toufiq Ul Amin
- Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, 95211, US
| | - Joshua S Ho
- Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, 95211, US
| | - Rasha Emara
- Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, 95211, US
| | - Arjun D Patel
- Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, 95211, US
| | - Melanie A Felmlee
- Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, 95211, US
| | - Miki S Park
- Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, 95211, US
| | - James A Uchizono
- Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, 95211, US
| | - Mamoun M Alhamadsheh
- Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, 95211, US.
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Hill R, Canals M. Experimental considerations for the assessment of in vivo and in vitro opioid pharmacology. Pharmacol Ther 2021; 230:107961. [PMID: 34256067 DOI: 10.1016/j.pharmthera.2021.107961] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/21/2021] [Accepted: 07/06/2021] [Indexed: 12/15/2022]
Abstract
Morphine and other mu-opioid receptor (MOR) agonists remain the mainstay treatment of acute and prolonged pain states worldwide. The major limiting factor for continued use of these current opioids is the high incidence of side effects that result in loss of life and loss of quality of life. The development of novel opioids bereft, or much less potent, at inducing these side effects remains an intensive area of research, with multiple pharmacological strategies being explored. However, as with many G protein-coupled receptors (GPCRs), translation of promising candidates from in vitro characterisation to successful clinical candidates still represents a major challenge and attrition point. This review summarises the preclinical animal models used to evaluate the key opioid-induced behaviours of antinociception, respiratory depression, constipation and opioid-induced hyperalgesia and tolerance. We highlight the influence of distinct variables in the experimental protocols, as well as the potential implications for differences in receptor reserve in each system. Finally, we discuss how methods to assess opioid action in vivo and in vitro relate to each other in the context of bridging the translational gap in opioid drug discovery.
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Affiliation(s)
- Rob Hill
- Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom; Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Midlands, United Kingdom.
| | - Meritxell Canals
- Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom; Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Midlands, United Kingdom.
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Díaz-Ruano S, López-Pérez AE, Girón R, Pérez-García I, Martín-Fontelles MI, Abalo R. Fluoroscopic Characterization of Colonic Dysmotility Associated to Opioid and Cannabinoid Agonists in Conscious Rats. J Neurogastroenterol Motil 2019; 25:300-315. [PMID: 30870877 PMCID: PMC6474695 DOI: 10.5056/jnm18202] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 02/01/2019] [Accepted: 02/12/2019] [Indexed: 12/25/2022] Open
Abstract
Background/Aims Gastrointestinal adverse effects have a major impact on health and quality of life in analgesics users. Non-invasive methods to study gastrointestinal motility are of high interest. Fluoroscopy has been previously used to study gastrointestinal motility in small experimental animals, but they were generally anesthetized and anesthesia itself may alter motility. In this study, our aim is to determine, in conscious rats, the effect of increasing doses of 2 opioid (morphine and loperamide) and 1 cannabinoid (WIN 55,212-2) agonists on colonic motility using fluoroscopic recordings and spatio-temporal maps. Methods Male Wistar rats received barium sulfate intragastrically, 20–22 hours before fluoroscopy, so that stained fecal pellets could be seen at the time of recording. Animals received an intraperitoneal administration of morphine, loperamide, or WIN 55,212-2 (at 0.1, 1, 5, or 10 mg/kg) or their corresponding vehicles (saline, Cremophor, and Tocrisolve, respectively), 30 minutes before fluoroscopy. Rats were conscious and placed within movement-restrainers for the length of fluoroscopic recordings (120 seconds). Spatio-temporal maps were built, and different parameters were analyzed from the fluoroscopic recordings in a blinded fashion to evaluate colonic propulsion of endogenous fecal pellets. Results The analgesic drugs inhibited propulsion of endogenous fecal pellets in a dose-dependent manner. Conclusions Fluoroscopy allows studying colonic propulsion of endogenous fecal pellets in conscious rats. Our method may be applied to the noninvasive study of the effect of different drug treatments and pathologies.
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Affiliation(s)
- Susana Díaz-Ruano
- Unidad de Dolor, Servicio de Anestesiología, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Ana E López-Pérez
- Unidad de Dolor, Servicio de Anestesiología, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Madrid, Spain
| | - Rocío Girón
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain.,Unidad Asociada I+D+i al Instituto de Investigación en Ciencias de la Alimentación, CIAL (CSIC), Madrid, Spain.,Unidad Asociada I+D+i al Instituto de Química Médica, IQM (CSIC), Madrid, Spain.,Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Madrid, Spain
| | - Irene Pérez-García
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
| | - María I Martín-Fontelles
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain.,Unidad Asociada I+D+i al Instituto de Investigación en Ciencias de la Alimentación, CIAL (CSIC), Madrid, Spain.,Unidad Asociada I+D+i al Instituto de Química Médica, IQM (CSIC), Madrid, Spain.,Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Madrid, Spain
| | - Raquel Abalo
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain.,Unidad Asociada I+D+i al Instituto de Investigación en Ciencias de la Alimentación, CIAL (CSIC), Madrid, Spain.,Unidad Asociada I+D+i al Instituto de Química Médica, IQM (CSIC), Madrid, Spain.,Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Madrid, Spain
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Niu Y, Wang J, Wang P, Guo X, Wang J, Kang W. Effect of Malus halliana Koehne Polysaccharides on Functional Constipation. OPEN CHEM 2018. [DOI: 10.1515/chem-2018-0107] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
AbstractThe effects of Malus halliana Koehne polysaccharides on functional constipation was investigated in this study. The rats were divided into six groups: normal group, model group, positive control group, M. halliana polysaccharides high dose groups 1200 mg/ kg, medium dose groups 1000 mg/ kg and low dose groups 800 mg/kg. The model of constipation was established by loperamide hydrochloride. Feces weight at 6 and 24 hours after treatment, Colon moisture content, in addition the levels of motilin (MTL), gastrin (Gas), somatostatin (SS), substance P (SP) in serum were used to evaluate the preventive effects of M. halliana polysaccharides on constipation. Compared with the model group, the positive control group, M. halliana polysaccharide high, medium and low dose group 6 h weight of feces, colon moisture content, the levels of motilin (MTL), gastrin (GAS) and substance P(SP) significantly (p <0.01) increased, the levels of somatostatin (SS) significantly decreased. The results indicated that the high, middle and low dosage of M. halliana polysaccharide could effectively improve functional constipation. Amongst these doses, the low dose group was better than others.
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Affiliation(s)
- Yingying Niu
- Joint International Research Laboratory of Food & Medicine Resource Function, Henan Province, Kaifeng475004, China; Kaifeng Key Laboratory of Functional Components in Health Food, Kaifeng475004, China
| | - Junya Wang
- Joint International Research Laboratory of Food & Medicine Resource Function, Henan Province, Kaifeng475004, China; Kaifeng Key Laboratory of Functional Components in Health Food, Kaifeng475004, China
| | - Pengyu Wang
- Institute of Chinese Materia Medica, Henan University, Kaifeng475004, China; Kaifeng Key Laboratory of Functional Components in Health Food, Kaifeng475004, China
| | - Xiuchun Guo
- Institute of Chinese Materia Medica, Henan University, Kaifeng475004, China; Kaifeng Key Laboratory of Functional Components in Health Food, Kaifeng475004, China
| | - Jinmei Wang
- Kaifeng Key Laboratory of Functional Components in Health Food, Kaifeng475004, China
| | - Wenyi Kang
- Joint International Research Laboratory of Food & Medicine Resource Function, Henan Province, Kaifeng475004, China; Institute of Chinese Materia Medica, Henan University, Kaifeng475004, China; Kaifeng Key Laboratory of Functional Components in Health Food, Kaifeng475004, China
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Yaoita F, Muto M, Murakami H, Endo S, Kozawa M, Tsuchiya M, Tadano T, Tan-No K. Involvement of peripheral alpha2A adrenoceptor in the acceleration of gastrointestinal transit and abdominal visceral pain induced by intermittent deprivation of REM sleep. Physiol Behav 2018; 186:52-61. [DOI: 10.1016/j.physbeh.2018.01.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 01/11/2018] [Accepted: 01/11/2018] [Indexed: 02/06/2023]
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Akel T, Bekheit S. Loperamide cardiotoxicity: "A Brief Review". Ann Noninvasive Electrocardiol 2017; 23:e12505. [PMID: 29125226 DOI: 10.1111/anec.12505] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 08/31/2017] [Indexed: 01/20/2023] Open
Abstract
Loperamide is a popular antidiarrheal medication that has been used for many years. It is currently gaining more attention among healthcare professionals due to its increasing potential for side effects. At present, it is considered safe enough to be sold over the counter. In contrast with other opioid agonists, loperamide is a peripherally acting μ-receptor agonist exerting its effects mainly on the myenteric plexus of the gastrointestinal longitudinal muscle layer. It decreases peristalsis and fluid secretion resulting in longer gastrointestinal transit time. The bioavailability of the drug is extremely low. Moreover, it is actively excluded from the central nervous system; hence, it lacks the central effects of euphoria and analgesia at the recommended dosages. Loperamide abuse has been steadily increasing in the United States. Abusers typically ingest high doses in desire to achieve a satisfactory central nervous system drug penetration. This has made it a potential over the counter substitute for self-treating opioid withdrawal symptoms and achieving euphoric effects.
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Affiliation(s)
- Tamer Akel
- Department of Internal Medicine, Staten Island University Hospital, Staten Island, NY, USA
| | - Soad Bekheit
- Department of Electrophysiology, Staten Island University Hospital, Staten Island, NY, USA
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Kim H, Kim I, Lee MC, Kim HJ, Lee GS, Kim H, Kim BJ. Effects of Hwangryunhaedok-tang on gastrointestinal motility function in mice. World J Gastroenterol 2017; 23:2705-2715. [PMID: 28487607 PMCID: PMC5403749 DOI: 10.3748/wjg.v23.i15.2705] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2016] [Revised: 02/22/2017] [Accepted: 03/20/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effects of Hwangryunhaedok-tang (HHT) on gastrointestinal (GI) motility in mice. METHODS The effects of a boiling water extract of HHT (HHTE) on GI motility were investigated by calculating percent intestinal transit rates (ITR%) and gastric emptying (GE) values using Evans Blue and phenol red, respectively, in normal mice and in mice with experimentally induced GI motility dysfunction (GMD). In addition, the effects of the four components of HHT, that is, Gardeniae Fructus (GF), Scutellariae Radix (SR), Coptidis Rhizoma (CR), and Phellodendri Cortex (PC), on GI motility were also investigated. RESULTS In normal ICR mice, ITR% and GE values were significantly and dose-dependently increased by the intragastric administration of HHTE (0.1-1 g/kg). The ITR% values of GMD mice were significantly lower than those of normal mice, and these reductions were significantly and dose-dependently inhibited by HHTE (0.1-1 g/kg). Additionally, GF, CR, and PC dose-dependently increased ITR% and GE values in normal and GMD mice. CONCLUSION These results suggest that HHT is a novel candidate for the development of a gastroprokinetic agent for the GI tract.
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“Poor man’s methadone” can kill the poor man. Extra-medical uses of loperamide: a review. Forensic Toxicol 2017. [DOI: 10.1007/s11419-017-0365-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Pérez-Vásquez A, Ángeles-López G, Cruz IR, Flores-Bocanegra L, Linares E, Bye R, Mata R. Spasmolytic Action of Preparations and Compounds from Hofmeisteria schaffneri. Nat Prod Commun 2017. [DOI: 10.1177/1934578x1701200401] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Hofmeisteria schaffneri is used in Mexican folk medicine for treating painful gastric complaints. Therefore, in this paper the smooth muscle relaxant effect of the essential oil, and an infusion of the whole plant were evaluated using the gastrointestinal transit test in mice. The results revealed that both preparations at 316 mg/kg inhibited gastrointestinal transit by 47.5 and 52.1%, respectively. The common component of the infusion and essential oil was 8,9-epoxy-10-acetoxythymol angelate (2), which inhibited the gastrointestinal transit by 53.4% at a dose of 31.6 mg/kg. An HPLC-UV method was developed and validated to quantify 2. The chromatographic conditions were: A LiChrospher® 100 RP-18 column (250 × 4 mm i.d., 5 μm) with a mobile phase composed of CH3CN-H2O, in a gradient run at a flow rate of 0.6 mL/min, using a wavelength of 215 nm. The method was linear, precise, accurate, and showed excellent recovery. According to the results, compound 2 can be used as a marker for the quality control procedures of the crude drug of H. schaffneri.
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Affiliation(s)
- Araceli Pérez-Vásquez
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, México
| | - Guadalupe Ángeles-López
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, México
| | - Isabel Rivero Cruz
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, México
| | - Laura Flores-Bocanegra
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, México
| | - Edelmira Linares
- Instituto de Biología, Universidad Nacional Autónoma de México, Ciudad de México 04510, México
| | - Robert Bye
- Instituto de Biología, Universidad Nacional Autónoma de México, Ciudad de México 04510, México
| | - Rachel Mata
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, México
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Abstract
Loperamide is widely available as an inexpensive, over-the-counter remedy commonly used for management of diarrhea. Although an opioid, at therapeutic doses it acts primarily on the gastrointestinal tissues; however, larger than recommended amounts facilitate central nervous system (CNS) penetration. Such high doses of loperamide have recently gained popularity among users of opioids to manage withdrawal symptomatology and, less frequently, to achieve psychoactive effects. Chronic loperamide use can result in development of tolerance and, upon abrupt cessation of use, withdrawal. With increasing prevalence of use, side-effects are noted, one particularly being life-threatening cardiac arrhythmias. Users are often not forthcoming and routine drug screens do not detect loperamide, so providers need to be alert to such practices in order to recognize intoxication, be able to screen for use, and facilitate entry into treatment.
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Affiliation(s)
- Cornel N Stanciu
- a Resident Physician, Department of Psychiatric Medicine, Brody School of Medicine , East Carolina University , Greenville , NC , USA
| | - Samantha A Gnanasegaram
- a Resident Physician, Department of Psychiatric Medicine, Brody School of Medicine , East Carolina University , Greenville , NC , USA
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Lee MC, Ha W, Park J, Kim J, Jung Y, Kim BJ. Effects of Lizhong Tang on gastrointestinal motility in mice. World J Gastroenterol 2016; 22:7778-7786. [PMID: 27678361 PMCID: PMC5016378 DOI: 10.3748/wjg.v22.i34.7778] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 06/07/2016] [Accepted: 07/31/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effects of Lizhong Tang, a traditional Chinese medicine formula, on gastrointestinal motility in mice. METHODS The in vivo effects of Lizhong Tang on GI motility were investigated by measuring the intestinal transit rates (ITRs) and gastric emptying (GE) values in normal mice and in mice with experimentally induced GI motility dysfunction (GMD). RESULTS In normal ICR mice, the ITR and GE values were significantly and dose-dependently increased by Lizhong Tang (ITR values: 54.4% ± 1.9% vs 65.2% ± 1.8%, P < 0.01 with 0.1 g/kg Lizhong Tang and 54.4% ± 1.9% vs 83.8% ± 1.9%, P < 0.01 with 1 g/kg Lizhong Tang; GE values: 60.7% ± 1.9% vs 66.8% ± 2.1%, P < 0.05 with 0.1 g/kg Lizhong Tang and 60.7% ± 1.9% vs 72.5% ± 1.7%, P < 0.01 with 1 g/kg Lizhong Tang). The ITRs of the GMD mice were significantly reduced compared with those of the normal mice, which were significantly and dose-dependently reversed by Lizhong Tang. Additionally, in loperamide- and cisplatin-induced models of GE delay, Lizhong Tang administration reversed the GE deficits. CONCLUSION These results suggest that Lizhong Tang may be a novel candidate for development as a prokinetic treatment for the GI tract.
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Kolbow J, Weitschies W, Siegmund W. Rapid Tolerance to Constipating Effects of Loperamide in Healthy Subjects. J Clin Pharmacol 2016; 56:248-9. [PMID: 26780488 DOI: 10.1002/jcph.659] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 10/12/2015] [Indexed: 01/21/2023]
Affiliation(s)
- Julia Kolbow
- Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine, Greifswald, Germany
| | - Werner Weitschies
- Department of Pharmaceutical Technology and Biopharmacy, Center of Drug Absorption and Transport, University of Greifswald, Greifswald, Germany
| | - Werner Siegmund
- Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine, Greifswald, Germany
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Auh QS, Chun YH, Melemedjian OK, Zhang Y, Ro JY. Peripheral interactions between cannabinoid and opioid receptor agonists in a model of inflammatory mechanical hyperalgesia. Brain Res Bull 2016; 125:211-7. [PMID: 27450703 DOI: 10.1016/j.brainresbull.2016.07.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 07/18/2016] [Accepted: 07/19/2016] [Indexed: 01/28/2023]
Abstract
Activation of opioid and cannabinoid receptors expressed in nociceptors induces effective antihyperalgesia. In this study, we examined whether combinations of opioid and cannabinoid receptor agonists directed at the injured site would enhance therapeutic effectiveness. Behavioral pharmacology experiments were performed to compare the effects of DAMGO, a selective agonist for μ-opioid receptor (MOR), ACPA, a specific agonist for CB1, and combinations of DAMGO and ACPA in attenuating complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia in the rat hindpaw. DAMGO (1μg-1mg) or ACPA (1μg-2mg) was administered into the inflamed paw when mechanical hyperalgesia was fully developed. When administered individually, DAMGO and ACPA dose-dependently reversed the mechanical hyperalgesia. DAMGO displayed a lower ED50 value (57.4±2.49μg) than ACPA (111.6±2.18μg), but ACPA produced longer lasting antihyperalgesic effects. Combinations of DAMGO and ACPA also dose-dependently attenuated mechanical hyperalgesia, but the antihyperalgesic effects were partial and transient even at high doses. Using isobolographic analysis, we determined that combined treatment with DAMGO and ACPA produced antagonistic effects with the observed ED50 of 128.4±2.28μg. Our findings showed that MOR and CB1 agonists directed at the inflamed site effectively attenuate mechanical hyperalgesia when administered individually, but exert opposing effects when administered together. The antagonistic interactions between the two classes of drugs at the inflamed site suggest distinct mechanisms unique to peripheral nociceptors or inflamed tissue, and therefore require further studies to investigate whether the therapeutic utility of the combined drug treatments in chronic pain conditions can be optimized.
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Affiliation(s)
- Q-Schick Auh
- Kyung Hee University, School of Dentistry, Department of Oral Medicine, 1 Hoegi Dong, Dongdaemun Gu, Seoul, Republic of Korea
| | - Yang Hyun Chun
- Kyung Hee University, School of Dentistry, Department of Oral Medicine, 1 Hoegi Dong, Dongdaemun Gu, Seoul, Republic of Korea
| | - Ohannes K Melemedjian
- University of Maryland School of Dentistry, Department of Neural and Pain Sciences, 650 W. Baltimore St., Baltimore, MD 21201, USA
| | - Youping Zhang
- University of Maryland School of Dentistry, Department of Neural and Pain Sciences, 650 W. Baltimore St., Baltimore, MD 21201, USA
| | - Jin Y Ro
- University of Maryland School of Dentistry, Department of Neural and Pain Sciences, 650 W. Baltimore St., Baltimore, MD 21201, USA; Kyung Hee University, School of Dentistry, Department of Oral Medicine, 1 Hoegi Dong, Dongdaemun Gu, Seoul, Republic of Korea.
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17
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Fatty Acids Analysis, Antioxidant and Biological Activity of Fixed Oil ofAnnona muricataL. Seeds. J CHEM-NY 2016. [DOI: 10.1155/2016/6948098] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The total oil yield and the fatty acid composition were determined in theAnnona muricataL. fixed oil using organic solvent extraction and GC-FID. The seeds were found to contain about ~21.5% of crude fixed oil on a dry weight basis. The crude oil containing fatty acid was converted into methyl esters and analysed by GC-FID. Fourteen fatty acids were identified using GC-FID. The major monounsaturated and saturated fatty acids were oleic acid (39.2%) and palmitic acid (19.1–19.2%), respectively, whereas theα-linolenic acid (1.2%) and linoleic acid (34.9%) were polyunsaturated fatty acid. The other saturated acids were stearic acid (3.3%), arachidic acid (0.4%), myristic acid (0.1%), heptadecanoic acid (0.1%), behenic acid (0.1%), and lignoceric acid (0.1%). Some of the fatty acids have not been reported earlier from the oil ofAnnona muricataL. Fixed oil exhibited significant free radical scavenging activity which was measured using DPPH and is also known to inhibit the gastrointestinal motility significantly.
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Abstract
Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly.
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Affiliation(s)
- Kwang Jae Lee
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
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Ahn TS, Kim DG, Hong NR, Park HS, Kim H, Ha KT, Jeon JH, So I, Kim BJ. Effects of Schisandra chinensis extract on gastrointestinal motility in mice. JOURNAL OF ETHNOPHARMACOLOGY 2015; 169:163-169. [PMID: 25862968 DOI: 10.1016/j.jep.2015.03.071] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 03/02/2015] [Accepted: 03/13/2015] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Schisandra chinensis (Turcz.) Baill. (SC) continues to be used as a traditional folk medicine in Asia, especially for the treatment of gastrointestinal (GI) disorders related to gastritis, diarrhea, enterocolitis and abnormal GI motility. AIM OF THE STUDY Because GI disorders, especially abnormal GI motility, are major lifelong problems, we investigated the effects of SC on the pacemaker activity of the interstitial cells of Cajal (ICCs) in murine small intestine and GI motility. MATERIALS AND METHODS Enzymatic digestions were used to dissociate ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record potentials generated by cultured ICCs. In vivo effects of SC on GI motility were investigated by measuring the intestinal transit rate (ITR) of Evans blue in normal and GI motility dysfunction mice. RESULTS SC extracts depolarized the membrane potentials of ICCs in a dose dependent manner. Pretreatment with Ca(2+) free solution or thapsigargin (a Ca(2+)-ATPase inhibitor in the endoplasmic reticulum) abolished the generation of pacemaker potentials by ICCs, and under these conditions, SC extract did not depolarize the membrane potentials of ICCs. In addition, membrane depolarizations were inhibited by intracellular GDPβS and by U-73122 (an active phospholipase C (PLC) inhibitor). In normal mice, ITRs were significantly increased by SC extract (0.1-1g/kg, intragastrically (i.g.)) in a dose dependent manner. Also, SC extract significantly recovered the GI motility dysfunctions in acetic acid (AA)-injected and streptozotocin (STZ)-induced diabetic mice, which are the GI motility animal models. MATERIALS AND METHODS SC extract modulates pacemaker potentials in ICCs in a dose dependent manner via external and internal Ca(2+) regulations, and via G protein and the PLC pathway. In addition, SC extract increased ITRs in normal and abnormal GI motility mice models. This study shows that SC extract offers a basis for the development of a prokinetic agent that prevents or alleviates GI motility dysfunctions.
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Affiliation(s)
- Tae Seok Ahn
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Dae Geon Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Noo Ri Hong
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Hyun Soo Park
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Hyungwoo Kim
- Division of Pharmacology, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Ki-Tae Ha
- Division of Applied Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Ju-Hong Jeon
- Department of Physiology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Insuk So
- Department of Physiology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea.
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Deiana S, Gabbani T, Bagnoli S, Annese V. Emerging drug for diarrhea predominant irritable bowel syndrome. Expert Opin Emerg Drugs 2015; 20:247-261. [PMID: 25732091 DOI: 10.1517/14728214.2015.1013935] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders with a 9 - 23% prevalence estimated in the general population. Patients can be subdivided into those who tend to have predominant diarrhea (IBS-D) or predominant constipation (IBS-C). Total annual productivity loss related to IBS in US is estimated at $205 million, with a significant impairment of health-related quality of life. A gold standard for the treatment of IBS is not established. Symptoms might improve with the use of few drugs and behavioral therapy, however, data concerning efficacy, safety and tolerability are limited. Therefore, development and validation of new therapies targeting at the molecular level are widely awaited. AREAS COVERED We will specifically describe in this review Phase II and Phase III trials, with specific focus on treatment of IBS-D patients. Unfortunately, it is difficult to draw definite conclusions from Phase II and Phase III trials, because of the known high placebo effect. EXPERT OPINION Drugs active on opioid receptor subtypes and neurokinin (NK) receptors seem to be the most promising, but substantial progress of information in this field is still needed. The achievement of more insights on the pathogenesis of IBS could surely better drive and target the therapy, but still strong efforts are awaited.
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Affiliation(s)
- Simona Deiana
- Emergency Department, Gastroenterology SOD2, AOU Careggi , Florence , Italy +39 55 7946035 ;
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Akbarali HI, Inkisar A, Dewey WL. Site and mechanism of morphine tolerance in the gastrointestinal tract. Neurogastroenterol Motil 2014; 26:1361-7. [PMID: 25257923 PMCID: PMC4423201 DOI: 10.1111/nmo.12443] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 08/24/2014] [Indexed: 12/23/2022]
Abstract
Opioid-induced constipation is a major clinical problem. The effects of morphine, and other narcotics, on the gastrointestinal tract persist over long-term use thus limiting the clinical benefit of these excellent pain relievers. The effects of opioids in the gut, including morphine, are largely mediated by the μ-opioid receptors at the soma and nerve terminals of enteric neurons. Recent studies demonstrate that regional differences exist in both acute and chronic morphine along the gastrointestinal tract. While tolerance develops to the analgesic effects and upper gastrointestinal motility upon repeated morphine administration, tolerance does not develop in the colon with chronic opioids resulting in persistent constipation. Here, we review the mechanisms by which tolerance develops in the small but not the large intestine. The regional differences lie in the signaling and regulation of the μ-opioid receptor in the various segments of the gastrointestinal tract. The differential role of β-arrestin2 in tolerance development between central and enteric neurons defines the potential for therapeutic approaches in developing ligands with analgesic properties and minimal constipating effects.
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Affiliation(s)
- H. I. Akbarali
- Department of Pharmacology and Toxicology; Virginia Commonwealth University; Richmond VA USA
| | - A. Inkisar
- Department of Pharmacology and Toxicology; Virginia Commonwealth University; Richmond VA USA
| | - W. L. Dewey
- Department of Pharmacology and Toxicology; Virginia Commonwealth University; Richmond VA USA
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Tonello R, Rigo F, Gewehr C, Trevisan G, Pereira EMR, Gomez MV, Ferreira J. Action of Phα1β, a peptide from the venom of the spider Phoneutria nigriventer, on the analgesic and adverse effects caused by morphine in mice. THE JOURNAL OF PAIN 2014; 15:619-31. [PMID: 24607814 DOI: 10.1016/j.jpain.2014.02.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Revised: 02/21/2014] [Accepted: 02/27/2014] [Indexed: 12/20/2022]
Abstract
UNLABELLED Opioids are standard therapy for the treatment of pain; however, adverse effects limit their use. Voltage-gated calcium channel blockers may be used to increase opioid analgesia, but their effect on opioid-induced side effects is little known. Thus, the goal of this study was to evaluate the action of the peptide Phα1β, a voltage-gated calcium channel blocker, on the antinociceptive and adverse effects produced by morphine in mice. A single administration of morphine (3-10 mg/kg) was able to reduce heat nociception as well as decrease gastrointestinal transit. The antinociception caused by a single injection of morphine was slightly increased by an intrathecal injection of Phα1β (30 pmol/site). Repeated treatment with morphine caused tolerance, hyperalgesia, withdrawal syndrome, and constipation, and the Phα1β (.1-30 pmol/site, intrathecal) was able to reverse these effects. Finally, the effects produced by the native form of Phα1β were fully mimicked by a recombinant version of this peptide. Taken together, these data show that Phα1β was effective in potentiating the analgesia caused by a single dose of morphine as well as in reducing tolerance and the adverse effects induced by repeated administration of morphine, indicating its potential use as an adjuvant drug in combination with opioids. PERSPECTIVE This article presents preclinical evidence for a useful adjuvant drug in opioid treatment. Phα1β, a peptide calcium channel blocker, could be used not only to potentiate morphine analgesia but also to reduce the adverse effects caused by repeated administration of morphine.
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Affiliation(s)
- Raquel Tonello
- Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Flávia Rigo
- Núcleo de Pós-graduação, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | - Camila Gewehr
- Núcleo de Pós-graduação, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | - Gabriela Trevisan
- Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil; Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
| | - Elizete Maria Rita Pereira
- Núcleo de Pós-graduação, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | - Marcus Vinicius Gomez
- Núcleo de Pós-graduação, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | - Juliano Ferreira
- Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil; Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
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Padmanabhan P, Grosse J, Asad ABMA, Radda GK, Golay X. Gastrointestinal transit measurements in mice with 99mTc-DTPA-labeled activated charcoal using NanoSPECT-CT. EJNMMI Res 2013; 3:60. [PMID: 23915679 PMCID: PMC3737085 DOI: 10.1186/2191-219x-3-60] [Citation(s) in RCA: 130] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Accepted: 07/25/2013] [Indexed: 11/10/2022] Open
Abstract
Background Gastrointestinal (GI) disorders are commonly associated with chronic conditions such as diabetes, obesity, and hypertension. Direct consequences are obstipation or diarrhea as opposite aspects of the irritable bowel syndrome, and more indirectly, alteration of appetite, feeling of fullness, flatulence, bloatedness, and eventually leading to altered absorption of nutrients. Moreover, GI retention and passage times have been recognized as important factors in determining the release site and hence the bioavailability of orally administered drugs. To facilitate the understanding of physiological and pathological processes involved, it is necessary to monitor the gut motility in animal models. Here, we describe a method for studying the GI transit time using technetium-labeled activated charcoal diethylenetriaminepentaacetic acid (99mTc-Ch-DTPA) detected by single-photon emission computed tomography (SPECT). Methods Tc-DTPA was adsorbed onto activated charcoal and administered orally to trypan blue-tainted (n = 4) 129SvEv mice (50 to 80 MBq/animal, n = 11). The exact distribution and movement of radioactivity in the gastrointestinal tract was measured at intervals of 1, 3, 6, 12, and 22 h by SPECT-CT. In addition, in order to validate the imaging of GI transient time, loperamide (0.25 mg/animal, n = 3) was used to delay the GI transit. Results The transit time measured as the peak radioactivity occurring in the rectum was 6 to 7 h after gavaging of 99mTc-Ch-DTPA. After 1 h, the bolus had passed into the small intestine and entered the cecum and the colon. At 6 and 8 h, the cecum, the ascending, transverse, and descending colon, and the rectum showed significant labeling. Several pellets were stored in the rectum for defecation. After 22 h, little activity remained in the stomach and none was detected in the transverse colon or other GI locations. In contrast, 6 h after administration of loperamide, only the cecum and part of the transverse colon were labeled. After 22 h, both structures retained significant amount of label. This delay has been verified by non-radiolabeled dye trypan blue GI measurements (n = 4). Conclusion Here, we present the first non-invasive study of mouse GI transit time, allowing clear differentiation between vehicle- and loperamide-treated animals. This technique is useful for the investigation of GI motility in mice.
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Affiliation(s)
- Parasuraman Padmanabhan
- Laboratory of Molecular Imaging, Singapore Bioimaging Consortium (SBIC), A*STAR, 11 Biopolis way, Singapore 138667, Singapore.
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Myagmarjalbuu B, Moon MJ, Heo SH, Jeong SI, Park JS, Jun JY, Jeong YY, Kang HK. Establishment of a protocol for determining gastrointestinal transit time in mice using barium and radiopaque markers. Korean J Radiol 2012; 14:45-50. [PMID: 23323030 PMCID: PMC3542302 DOI: 10.3348/kjr.2013.14.1.45] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Accepted: 07/05/2012] [Indexed: 01/26/2023] Open
Abstract
Objective The purpose of this study was to establish a minimally invasive and reproducible protocol for estimating the gastrointestinal (GI) transit time in mice using barium and radiopaque markers. Materials and Methods Twenty 5- to 6-week-old Balb/C female mice weighing 19-21 g were used. The animals were divided into three groups: two groups that received loperamide and a control group. The control group (n = 10) animals were administered physiological saline (1.5 mL/kg) orally. The loperamide group I (n = 10) and group II (n = 10) animals were administered 5 mg/kg and 10 mg/kg loperamide orally, respectively. Thirty minutes after receiving the saline or loperamide, the mice was administered 80 µL of barium solution and six iron balls (0.5 mm) via the mouth and the upper esophagus by gavage, respectively. Afterwards, the mice were continuously monitored with fluoroscopic imaging in order to evaluate the swallowing of the barium solution and markers. Serial fluoroscopic images were obtained at 5- or 10-min intervals until all markers had been excreted from the anal canal. For analysis, the GI transit times were subdivided into intestinal transit times (ITTs) and colon transit times (CTTs). Results The mean ITT was significantly longer in the loperamide groups than in the control group (p < 0.05). The mean ITT in loperamide group II (174.5 ± 32.3) was significantly longer than in loperamide group I (133.2 ± 24.2 minute) (p < 0.05). The mean CTT was significantly longer in loperamide group II than in the control group (p < 0.05). Also, no animal succumbed to death after the experimental procedure. Conclusion The protocol for our study using radiopaque markers and barium is reproducible and minimally invasive in determining the GI transit time of the mouse model.
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Affiliation(s)
- Bolormaa Myagmarjalbuu
- Department of Radiology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun 519-763, Korea
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Matarese LE. Nutrition and Fluid Optimization for Patients With Short Bowel Syndrome. JPEN J Parenter Enteral Nutr 2012; 37:161-70. [DOI: 10.1177/0148607112469818] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Chung C, Carteret AF, McKelvy AD, Ringkamp M, Yang F, Hartke TV, Dong X, Raja SN, Guan Y. Analgesic properties of loperamide differ following systemic and local administration to rats after spinal nerve injury. Eur J Pain 2012; 16:1021-32. [PMID: 22508374 DOI: 10.1002/j.1532-2149.2012.00148.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2012] [Indexed: 01/24/2023]
Abstract
BACKGROUND The analgesic properties and mechanisms of loperamide hydrochloride, a peripherally acting opioid receptor agonist, in neuropathic pain warrant further investigation. METHODS We examined the effects of systemic or local administration of loperamide on heat and mechanical hyperalgesia in rats after an L5 spinal nerve ligation (SNL). RESULTS (1) Systemic loperamide (0.3-10 mg/kg, subcutaneous in the back) dose dependently reversed heat hyperalgesia in SNL rats, but did not produce thermal analgesia. Systemic loperamide (3 mg/kg) did not induce thermal antinociception in naïve rats; (2) systemic loperamide-induced anti-heat hyperalgesia was blocked by pretreatment with intraperitoneal naloxone methiodide (5 mg/kg), but not by intraperitoneal naltrindole (5 mg/kg) or intrathecal naltrexone (20 μg/10 μL); (3) local administration of loperamide (150 μg), but not vehicle, into plantar or dorsal hind paw tissue induced thermal analgesia in SNL rats and thermal antinociception in naïve rats; (4) the analgesic effect of intraplantar loperamide (150 μg/15 μL) in SNL rats at 45 min, but not 10 min, post-injection was blocked by pretreatment with an intraplantar injection of naltrexone (75 μg/10 μL); (5) systemic (3.0 mg/kg) and local (150 μg) loperamide reduced the exaggerated duration of hind paw elevation to noxious pinprick stimuli in SNL rats. Intraplantar injection of loperamide also decreased the frequency of pinprick-evoked response in naïve rats. CONCLUSIONS These findings suggest that both systemic and local administration of loperamide induce an opioid receptor-dependent inhibition of heat and mechanical hyperalgesia in nerve-injured rats, but that local paw administration of loperamide also induces thermal and mechanical antinociception.
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Affiliation(s)
- C Chung
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, USA
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Lima-Júnior RCP, Figueiredo AA, Freitas HC, Melo MLP, Wong DVT, Leite CAVG, Medeiros RP, Marques-Neto RD, Vale ML, Brito GAC, Oriá RB, Souza MHLP, Cunha FQ, Ribeiro RA. Involvement of nitric oxide on the pathogenesis of irinotecan-induced intestinal mucositis: role of cytokines on inducible nitric oxide synthase activation. Cancer Chemother Pharmacol 2011; 69:931-42. [PMID: 22101361 DOI: 10.1007/s00280-011-1780-z] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Accepted: 11/07/2011] [Indexed: 12/17/2022]
Abstract
PURPOSE Intestinal mucositis and the closely associated diarrhea are common costly side effects of irinotecan. Cytokine modulators, such as thalidomide and pentoxifylline, are found capable of attenuating intestinal mucositis progression. Nitric oxide (NO) seems to be a key mediator of the antineoplastic drug toxicity. The aim of this study was to investigate the role of NO on the pathogenesis of intestinal mucositis, as well as the participation of cytokines upon inducible nitric oxide synthase (iNOS) expression in irinotecan-induced intestinal mucositis. METHODS iNOS-knockout (iNOS(-/-)) and C57BL/6 (WT, wild type) animals (n = 5-6) were given either saline or irinotecan (60 mg/kg i.p for 4 days), with or without pretreatment with aminoguanidine (50 mg/kg s.c.), thalidomide (60 mg/kg s.c), infliximab (5 mg/kg i.v.), or pentoxifylline (1.7 mg/kg s.c). On day 5, diarrhea was assessed, and following euthanasia, proximal intestinal samples were obtained for myeloperoxidase (MPO) and iNOS activity, morphometric analysis, western blot and immunohistochemistry to iNOS, cytokine dosage, and for in vitro evaluation of gut contractility. RESULTS Irinotecan induced severe diarrhea and intestinal smooth muscle over-contractility, accompanied with histopathological changes. Additionally, increased MPO and iNOS activity and iNOS immunoexpression were found in WT animals treated with irinotecan. The rise in MPO, smooth muscle over-contractility, and diarrhea were abrogated in aminoguanidine-treated and iNOS(-/-) mice. Moreover, through western blot, we verified that infliximab and pentoxifylline significantly inhibited irinotecan-induced iNOS expression. In addition, cytokine concentration was found only partially decreased in irinotecan-treated iNOS(-/-) mice when compared with wild-type animals that were given irinotecan. CONCLUSIONS This study suggests a role of nitric oxide in the pathogenesis of irinotecan-induced intestinal mucositis and also provides evidence for the participation of cytokines on iNOS induction.
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Affiliation(s)
- Roberto César P Lima-Júnior
- Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Rua Cel Nunes de Melo, 1315 Rodolfo Teófilo, Fortaleza, Ceará 60430-270, Brazil
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Rivero-Cruz I, Duarte G, Navarrete A, Bye R, Linares E, Mata R. Chemical composition and antimicrobial and spasmolytic properties of Poliomintha longiflora and Lippia graveolens essential oils. J Food Sci 2011; 76:C309-17. [PMID: 21535751 DOI: 10.1111/j.1750-3841.2010.02022.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
UNLABELLED In the present study, we reported a comparative analysis of the chemical composition and pharmacological properties of the essential oils obtained from 2 Mexican oreganos, Poliomintha longiflora and Lippia graveolens. The gas chromatography-mass spectrometry (GC-MS) profiles of the oils showed high amounts of oxygenated monoterpenes, mainly carvacrol (%[mg/100 g dry matter]) (18.36 [459.0] in P. longiflora and 13.48 [164.7] in L. graveolens). In addition, these oils contained marked quantities of p-cymene (14.09 [352.2] and 7.46 [37.3], respectively), β-caryophyllene oxide, β-caryophyllene, and carvacrol acetate. Headspace analyses of the leaves of both species using different coated fibers revealed that γ-terpinene, eucalyptol, and p-cymene were the principal light volatile components. Chromatographic fingerprints and a suitable analytical method for quantifying the main components of both essences were established using high-performance liquid chromatography (HPLC) as analytical tool. The essential oils of both species were not toxic in the acute toxicity studies in mice performed according to the Lorke procedure (DL(50) > 5000 mg/kg). The oils and the major constituents, carvacrol and p-cymene, displayed a moderate in vitro antibacterial activity, with minimum inhibitory concentration values ranging from 128 to 512 μg/mL. In addition, these samples demonstrated a marginal antispasmodic activity in vivo and provoked a concentration-dependent inhibition of the carbachol- and histamine-induced contractions using the isolated guinea-pig ileum preparation. In particular, p-cymene exerts good selective inhibitory activity on the carbachol-induced contractions (IC(50) = 9.85 μg/mL). PRACTICAL APPLICATION The analytical methods using GC-MS and HPLC techniques will be useful for establishing quality control as well as preclinical pharmacological and toxicological parameters of the crude drug P. longiflora, which is widely used as substitute of L. graveolens for medicinal and flavorings purposes. This overall information will be also useful for elaborating scientific and pharmacopoeic monographs of this very Mexican medicinal plant.
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Affiliation(s)
- Isabel Rivero-Cruz
- Facultad de Química, Univ. Nacional Autónoma de México, México DF, Coyoacán 04360, México
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Yuan CS, Foss JF, Williams WA, Moss J. Development and use of methylnaltrexone, a peripherally acting opioid antagonist, to treat side effects related to opioid use. Drug Dev Res 2009. [DOI: 10.1002/ddr.20318] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Abstract
Constipation is a significant problem related to opioid medications used to manage pain. This review attempts to outline the latest findings related to the therapeutic usefulness of a μ opioid receptor antagonist, methylnaltrexone in the treatment of opioid-induced constipation. The review highlights methylnaltrexone bromide (Relistor™; Progenics/Wyeth) a quaternary derivative of naltrexone, which was recently approved in the United States, Europe and Canada. The Food and Drug Administration in the United States approved a subcutaneous injection for the treatment of opioid bowel dysfunction in patients with advanced illness who are receiving palliative care and when laxative therapy has been insufficient. Methylnaltrexone is a peripherally restricted, μ opioid receptor antagonist that accelerates oral-cecal transit in patients with opioid-induced constipation without reversing the analgesic effects of morphine or inducing symptoms of opioid withdrawal. An analysis of the mechanism of action and the potential benefits of using methylnaltrexone is based on data from published basic research and recent clinical studies.
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Affiliation(s)
- Beverley Greenwood-Van Meerveld
- Veterans Affairs Medical Center, Oklahoma Center for Neuroscience, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Kelly M Standifer
- Department of Pharmaceutical Sciences, Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
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Ross GR, Gabra BH, Dewey WL, Akbarali HI. Morphine tolerance in the mouse ileum and colon. J Pharmacol Exp Ther 2008; 327:561-72. [PMID: 18682567 PMCID: PMC2574683 DOI: 10.1124/jpet.108.143438] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Repeated administration of morphine is associated with tolerance to its antinociceptive properties. However, constipation remains the major side effect of chronic exposure to morphine. In contrast, previous studies suggest that tolerance to opioids develops in the ileum of several species. In this study, we provide evidence that constipation may arise due to a lack of tolerance development to morphine in the colon. Mice received implants with either placebo or 75 mg of morphine pellets, and they were examined for morphine tolerance to antinociception, defecation, and intestinal and colonic transit after 72 h. Tissues were obtained from the ileum and distal colon, and contractile responses were measured from longitudinal and circular muscle preparations. In morphine-pelleted mice, a 5.5-fold tolerance developed to antinociception after 72 h, and a 53.2-fold tolerance developed in mice that received an additional daily morphine injection. In both models, intestinal transit but not defecation or colonic transit developed tolerance. In isolated longitudinal muscles, electrical field stimulation-induced cholinergic contractions were dose-dependently inhibited by morphine in both the ileum and colon of placebo pelleted with a pD(2) of 7.1 +/- 0.4 and 7.8 +/- 0.4, respectively. However, the dose response to morphine inhibition was shifted to the right for the ileum from morphine-pelleted mice (pD(2) = 5.1 +/- 0.4) but not the colon (pD(2) = 6.9 +/- 0.4). In circular muscle preparations, morphine induced atropine-insensitive contractions in both tissue segments. Tolerance to morphine developed in the ileum but not the colon upon repeated administration of morphine. These findings indicate that a lack of tolerance development in the colon is the basis for opioid bowel dysfunction.
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Affiliation(s)
- Gracious R Ross
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA
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Gallantine EL, Meert TF. Antinociceptive and Adverse Effects of µ- and κ-Opioid Receptor Agonists: A Comparison of Morphine and U50488-H. Basic Clin Pharmacol Toxicol 2008; 103:419-27. [DOI: 10.1111/j.1742-7843.2008.00306.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Tucci P, Palmery M, Piccolotti P, Pimpinella G, Valeri P, Romanelli L. Counteracting effect of papaverine on morphine inhibition of gastrointestinal transit in mice. Neurogastroenterol Motil 2008; 20:958-65. [PMID: 18363637 DOI: 10.1111/j.1365-2982.2008.01103.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Oral papaverine has been shown to be capable of antagonizing the constipation induced by a single dose of oral morphine. The primary aim of the present study was to ascertain whether papaverine is also capable of counteracting morphine-induced decrease of upper gastrointestinal transit (UGT) after repeated parenteral administration of the opioid. We next investigated the mechanisms(s) responsible for the counteracting effect of papaverine, by analysing whether this effect was changed by pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME), dexamethasone, indomethacin or capsaicin. Papaverine, co-administered with morphine, counteracted the morphine-induced decrease in UGT in mice pretreated with morphine for 3 days but did not do so in naive animals. The counteracting effect of papaverine was antagonized by L-NAME, but not by indomethacin. In mice pretreated with both morphine and dexamethasone, papaverine failed to antagonize the effect of morphine. Capsaicin pretreatment completely abolished the effect of a single dose of morphine, the effect being partially restored by the 3 days pretreatment with morphine. In mice pretreated with both capsaicin and morphine, the UGT decrease elicited by morphine was lower than in the other experimental groups and was not modified by papaverine. Our results show that papaverine can counteract the morphine inhibition of UGT in mice repeatedly exposed to the opioid. Papaverine exerts its action through a nitric oxide synthase-mediated mechanism; this mechanism is only effective after repeated morphine administration and does not operate when capsaicin-sensitive afferent neurones are ablated.
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Affiliation(s)
- P Tucci
- Department of Biomedical Sciences, University of Foggia, School of Medicine, Foggia, Italy.
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Barone FC, Barton ME, White RF, Legos JJ, Kikkawa H, Shimamura M, Kuratani K, Kinoshita M. Inhibition of Phosphodiesterase Type 4 Decreases Stress-Induced Defecation in Rats and Mice. Pharmacology 2007; 81:11-7. [PMID: 17726343 DOI: 10.1159/000107662] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2007] [Accepted: 05/02/2007] [Indexed: 12/14/2022]
Abstract
BACKGROUND/AIMS Phosphodiesterase type 4 (PDE4) has been previously shown to regulate colonic contractile activity in vitro. In this study, the effects of PDE4 inhibition were assessed in a model of stress-induced defecation previously demonstrated to be due to increased colonic transit/evacuation. METHODS Rats were individually placed in a mild restraint cage and placed into a 12 degrees C environment (cold-restraint stress) for 60 min. Mice received restraint (only) stress at room temperature for 30 min. Loperamide (positive control compound) or two different PDE4 inhibitors (rolipram and roflumilast) were administered orally at several doses to the rodents 1 h before stress began. Vehicle alone was administered for comparison. The number of fecal pellets expelled during stress (fecal pellet output), total fecal pellet wet weight and total fecal water content were measured. RESULTS Loperamide produced a dose-related decrease (ID(50)s in mg/kg) in fecal pellet output (rat = 7.4, mouse = 0.7) and significantly decreased fecal wet weight (72.9%) and decreased fecal percent water content (9.4%). The two PDE4 inhibitors produced a similar dose-related inhibition of fecal pellet output. Rolipram exhibited ID(50)s in rat and mouse of 14.1 and 27.1, respectively. Rolipram significantly decreased fecal wet weight (58.8%) but increased fecal percent water content (15.0%). For roflumilast, ID(50)s were 24.2 mg/kg and 12.4 in the rat and mouse, respectively. Although roflumilast also significantly (p < 0.05) decreased fecal wet weight (47.2%), it did not significantly increase fecal percent water content. CONCLUSIONS These data indicate that PDE4 inhibition is effective in reducing rodent stress-induced defecation, provides the first functional data on a potential role for PDE4 activity in the colonic evacuation response to stress, and indicates the potential utility of PDE4 inhibitors in functional bowel disease such as irritable bowel syndrome requires further evaluation.
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Affiliation(s)
- Frank C Barone
- Discovery Research, High Throughput Biology, GlaxoSmithKline, King of Prussia, PA 19406, USA.
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Iwata H, Tsuchiya S, Nakamura T, Yano S. Morphine leads to contraction of the ileal circular muscle via inhibition of the nitrergic pathway in mice. Eur J Pharmacol 2007; 574:66-70. [PMID: 17632101 DOI: 10.1016/j.ejphar.2007.06.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2007] [Revised: 05/11/2007] [Accepted: 06/12/2007] [Indexed: 01/28/2023]
Abstract
Morphine inhibits small intestinal transit in mice, although few mu-opioid receptors are present in the ileum. The present study focused on the action of morphine in the isolated mouse ileum to reveal the mechanism by which morphine inhibits mouse small intestinal transit. In the isolated circular muscle, morphine caused tonic contraction. This contraction was potently inhibited by naloxone and the mu-opioid receptor antagonist cyprodime. Moreover, the response was almost completely inhibited by tetrodotoxin and N(G)-nitro-L-arginine, but only moderately inhibited by atropine and indomethacin. In the isolated longitudinal muscle, morphine caused no or only slight contractions. Furthermore, electrically induced contraction was dose-dependently depressed by morphine, an effect that was not reversed by naloxone. These findings indicate that 1) morphine-induced circular muscle contraction occurs in the mouse ileum, 2) the contraction occurs through mu-opioid receptors mainly by inhibiting the release of nitric oxide from nitrergic nerves, although cholinergic nerves are at least partly involved in this contractile mechanism, and 3) inhibition of descending relaxation of peristalsis by morphine may slow small intestinal transit.
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Affiliation(s)
- Hiroki Iwata
- Laboratory of Molecular Pharmacology and Pharmacotherapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
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Yuan CS. Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects. Ann Pharmacother 2007; 41:984-93. [PMID: 17504835 DOI: 10.1345/aph.1k009] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
OBJECTIVE To review the mechanisms of action of methylnaltrexone and its effects on opioid bowel dysfunction, as well as its effects on other opioid-induced adverse effects (ADEs), and its potential roles in clinical practice. DATA SOURCES A literature search using the MEDLINE and Cochrane Collaboration databases for articles published between 1966 and March 2007 was performed. Additional data sources were obtained from manual searches of recent journal articles, book chapters, and monographs. An updated literature search showed no additional publications. STUDY SELECTION AND DATA EXTRACTION Abstracts and original preclinical and clinical research reports published in the English language were identified for review. Review articles, commentaries, and news reports of this compound were excluded. Literature related to opioids, opioid receptors, opioid antagonists, methylnaltrexone, opioid-induced bowel dysfunction, constipation, nausea, and vomiting was evaluated and selected based on consideration of the support shown for the proof of concept, mechanistic findings, and timeliness. Fifty-eight original articles from preclinical studies and clinical trials using methylnaltrexone were identified. Pharmacologic action, benefits, and ADEs of methylnaltrexone were reviewed, with a focus on its effects on bowel dysfunction after opioids. Emphases were placed on its receptor binding activities and therapeutically relevant sites of action (peripheral vs central), in which peripheral opioid receptors in the body contribute to physiological and drug-induced effects. DATA SYNTHESIS Morphine and related opioids are associated with a number of limiting ADEs, including opioid-induced bowel dysfunction. Methylnaltrexone, a quaternary derivative of naltrexone, blocks peripheral effects of opioids while sparing central analgesic effects. It is currently under late-stage clinical investigation for the treatment of opioid-induced constipation in patients with advanced illness. Reported results showed the drug to be generally well-tolerated. The rapid reversal of constipation is very encouraging. Hastening postoperative discharge may also be possible. CONCLUSIONS Methylnaltrexone has the potential to prevent or treat opioid-induced peripherally mediated ADEs on bowel dysfunction without interfering with central analgesia. The study of methylnaltrexone leads to a greater understanding of the mechanisms of action of opioid pharmacology.
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Affiliation(s)
- Chun-Su Yuan
- Department of Anesthesia & Critical Care, Pritzker School of Medicine, The University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637, USA.
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Andersen YS, Gillin FD, Eckmann L. Adaptive immunity-dependent intestinal hypermotility contributes to host defense against Giardia spp. Infect Immun 2006; 74:2473-6. [PMID: 16552082 PMCID: PMC1418922 DOI: 10.1128/iai.74.4.2473-2476.2006] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Humans infected with Giardia exhibit intestinal hypermotility, but the underlying mechanisms and functional significance are uncertain. Here we show in murine models of giardiasis that small-intestinal hypermotility occurs in a delayed fashion relative to peak parasite burden, is dependent on adaptive immune defenses, and contributes to giardial clearance.
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Affiliation(s)
- Yolanda S Andersen
- Department of Medicine 0665, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0665, USA
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Abstract
Use of opioid analgesics is associated with a number of side effects, especially opioid-induced gastrointestinal dysfunction. The extensive use of these compounds and the significant negative impact of the resulting gastrointestinal dysfunction on patients' quality of life make it an important clinical issue. In recent years our understanding of the mechanisms of opioid-induced gastrointestinal dysfunction has advanced greatly. This article reviews the underlying pathophysiological mechanisms of specific gastrointestinal adverse effects of opioids. The role of endogenous opioid peptides in certain gastrointestinal diseases is also discussed. A better understanding of the pathophysiological mechanisms of opioid-induced bowel dysfunction should lead to the development of newer opioid analgesics and improved regimens resulting in reduced gastrointestinal adverse effects.
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Affiliation(s)
- Sangeeta R Mehendale
- Department of Anesthesia and Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA
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Gallantine EL, Meert TF. A Comparison of the Antinociceptive and Adverse Effects of the mu-Opioid Agonist Morphine and the delta-Opioid Agonist SNC80. Basic Clin Pharmacol Toxicol 2005; 97:39-51. [PMID: 15943758 DOI: 10.1111/j.1742-7843.2005.pto_97107.x] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
delta-Opioid receptor agonists have been postulated to induce analgesia without the adverse effects commonly associated with mu-opioids e.g. morphine. In the present study, we evaluated the occurrence of antinociceptive and opioid-like side effects in rats (n=5-7) treated with a single dose of subcutaneous morphine (0.01 to 40 mg/kg) or SNC80 (0.63 to 80 mg/kg). The antinociceptive effects of morphine and SNC80 were compared using a range of nociceptive tests including the tail withdrawal test, the acetic acid-induced abdominal constriction (writhing) assay, the automated formalin test and a model of inflammation-induced thermal hyperalgesia. The adverse effects of both drugs were examined in animal models for gastrointestinal (GI) inhibition (charcoal test; ricinus oil test), respiratory depression (blood-gas analysis), motor disturbances (automated rotarod model) and abuse liability (drug discrimination learning). Morphine displayed significant antinociceptive and adverse effects in all the animal models employed. SNC80 exhibited a significant effect in the writhing test and limited efficacy in a model of inflammation-induced thermal hypersensitivity. A delay in the occurrence of diarrhoea and some limited increases in PCO(2) were observed with the higher doses of SNC80 (> or =40 mg/kg). In conclusion, the delta-opioid agonist SNC80 lacks both the analgesic efficacy and adverse effects of mu-opioids. However, the activity of SNC80 in the inflammatory model suggests delta-opioid agonists may be useful analgesics in the treatment of some forms of inflammatory pain.
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Affiliation(s)
- Elizabeth L Gallantine
- CNS Discovery Research, Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
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Abstract
This paper is the 26th consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over a quarter-century of research. It summarizes papers published during 2003 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).
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Affiliation(s)
- Richard J Bodnar
- Department of Psychology and Neuropsychology, Doctoral Sub-Program, Queens College, City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, USA.
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Lin L, Xu HC, Zhang HJ, Hu YD, Lin Z, Zhao ZQ. Alterations of Cajal cell in colon of slow transit constipation mice. Shijie Huaren Xiaohua Zazhi 2004; 12:2107-2110. [DOI: 10.11569/wcjd.v12.i9.2107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish an animal model of slow transit constipation and to investigate the relationship between interstitial cell of Cajal in colon and the pathophysiological changes in the model of slow transit constipation.
METHODS: The mouse model was established by subcutaneous injection of morphine. According to period of morphine injected, the mice were divided into two groups: 2.5 mg/kg/per day ×30 d (n = 15) and 2.5 mg/kg/per day ×45 d (n = 15), and corresponding control groups were established by injecting the same dosage of 9 g/L sodium chloride solution. Fecal weight was recorded daily, and transit function of intestine was measured by activated charcoal suspension pushing test. The changes of interstitial cell of Cajal were observed by immunohistochemistry.
RESULTS: Fecal weight daily in test groupⅠwas less than control groupⅠ(18.8±3.2 g vs 20.6±1.8 g, P <0.05), and test groupⅡwas less than control group Ⅱ (16.8±2.0 g vs 22.0±3.2 g, P <0.01). It showed the significance of difference between the test groupⅠvs test groupⅡ(P <0.05), and no difference between two control groups (P >0.05). Intestinal transit rate in test group Ⅰwas lower than control groupⅠ(45.3±1.5% vs 49.2±1.8%, P <0.05), and test group Ⅱwas lower than control groupⅡ(40.6±1.3% vs 50.6±3.0%, P <0.01). There was a significant difference between test groupⅠvs test groupⅡ(P <0.05), and no difference between two control groups (P >0.05). Colon tissue c-kit+ cell's area in test groupⅠwas more decreased than that of control groupⅠ(81.3±7.9 ten thousand mm2vs 98.6±8.0 ten thousand mm2, P <0.01), and test group Ⅱvs control groupⅡwas 66.5±8.4 vs 100.9±10.0 ten thousand mm2 (P <0.01). There was a significant difference between the testⅠand testⅡ(P <0.01),and no difference in two control groups (P >0.05).
CONCLUSION: Daily fecal mass, intestinal transit ratio and the number of interstitial cells of Cajal are decreased in the mouse model of slow intestinal transit movement induced by morphine and have a positive correlation with period of morphine injected.
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Liu BH, Mo P, Zhang SB. Effects of mu and kappa opioid receptor agonists and antagonists on contraction of isolated colon strips of rats with cathartic colon. World J Gastroenterol 2004; 10:1672-4. [PMID: 15162549 PMCID: PMC4572778 DOI: 10.3748/wjg.v10.i11.1672] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To study the effects of mu and kappa opioid receptor agonists and antagonists on the isolated colon strips of rats with cathartic colon.
METHODS: Cathartic colon model was established by feeding rats with contact laxatives, and effects of mu and kappa opioid receptor agonists and antagonists on electricity-stimulated contraction of isolated colon strips of rats with cathartic colon were observed.
RESULTS: Compared with control group, exogenous mu and kappa agonists inhibited significantly electricity-stimulated contraction of strips of cathartic colon (8.50 ± 0.89 mm, 6.24 ± 0.91 mm, 3.35 ± 0.6 mm vs 11.40 ± 0.21 mm P < 0.01; 8.98 ± 0.69 mm, 6.89 ± 0.71 mm, 4.43 ± 0.99 mm vs 11.40 ± 0.21 mm, P < 0.01). In contrast, the exogenous mu antagonist significantly enhanced electricity-stimulated contraction of isolated colon strips (13.18 ± 0.93 mm, 15.87 ± 0.98 mm, 19.46 ± 1.79 mm vs 11.40 ± 0.21 mm, P < 0.01), but kappa antagonist had no effect on the isolated colon strips of rats with cathartic colon.
CONCLUSION: Mu and kappa opioid receptors are involved in the regulation of colon motility of rats with cathartic colon.
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MESH Headings
- Analgesics, Opioid/pharmacology
- Animals
- Cathartics/pharmacology
- Colon/drug effects
- Colon/physiology
- Colonic Diseases, Functional/chemically induced
- Colonic Diseases, Functional/drug therapy
- Colonic Diseases, Functional/physiopathology
- Constipation/drug therapy
- Electric Stimulation
- Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology
- Female
- Gastrointestinal Motility/drug effects
- In Vitro Techniques
- Male
- Muscle Contraction/drug effects
- Naloxone/pharmacology
- Narcotic Antagonists/pharmacology
- Rats
- Rats, Wistar
- Receptors, Opioid, kappa/agonists
- Receptors, Opioid, kappa/antagonists & inhibitors
- Receptors, Opioid, kappa/metabolism
- Receptors, Opioid, mu/agonists
- Receptors, Opioid, mu/antagonists & inhibitors
- Receptors, Opioid, mu/metabolism
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Affiliation(s)
- Bao-Hua Liu
- Department of General Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
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