title: Role of peripheral endothelin receptors in an animal model of complex regional pain syndrome type 1 (CRPS-I).
abstract: Chronic post-ischemic pain (CPIP) is an animal model of CRPS-I developed using a 3-h ischemia-reperfusion injury of the rodent hind paw. The contribution of local endothelin to nociception has been evaluated in CPIP mice by measuring sustained nociceptive behaviors (SNBs) following intraplantar injection of endothelin-1 or -2 (ET-1, ET-2). The effects of local BQ-123 (ETA-R antagonist), BQ-788 (ETB-R antagonist), IRL-1620 (ETB-R agonist) and naloxone (opioid antagonist) were assessed on ET-induced SNBs and/or mechanical and cold allodynia in CPIP mice. ETA-R and ETB-R expression was assessed using immunohistochemistry and Western blot analysis. Compared to shams, CPIP mice exhibited hypersensitivity to local ET-1 and ET-2. BQ-123 reduced ET-1- and ET-2-induced SNBs in both sham and CPIP animals, but not mechanical or cold allodynia. BQ-788 enhanced ET-1- and ET-2-induced SNBs in both sham and CPIP mice, and cold allodynia in CPIP mice. IRL-1620 displayed a non-opioid anti-nociceptive effect on ET-1- and ET-2-induced SNBs and mechanical allodynia in CPIP mice. The distribution of ETA-R and ETB-R was similar in plantar skin of sham and CPIP mice, but both receptors were over-expressed in plantar muscles of CPIP mice. This study shows that ETA-R and ETB-R have differing roles in nociception for sham and CPIP mice. CPIP mice exhibit more local endothelin-induced SNBs, develop a novel local ETB-R agonist-induced (non-opioid) analgesia, and exhibit over-expression of both receptors in plantar muscles, but not skin. The effectiveness of local ETB-R agonists as anti-allodynic treatments in CPIP mice holds promise for novel therapies in CRPS-I patients.
authors.affiliation: Department of Anesthesia, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6 Department of Neurology & Neurosurgery, McGill University, 3801 University Ave., Montreal, Quebec, Canada H3A 2B4 Department of Psychology, McGill University, 1205 Dr. Penfield Ave., Montreal, Quebec, Canada H3A 1B1 Department of Pharmacology & Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6 Faculty of Dentistry, McGill University, 3640 University Ave., Montreal, Quebec, Canada H3A 2B2 Alan Edwards Centre for Research on Pain, McGill University, 740 Dr. Penfield Ave., Montreal, Quebec, Canada H3A 1A4 McGill University Health Centre Research Institute, 2155 Guy St., Montreal, Quebec, Canada H3H 2R9.
authors.forename: Magali
authors.initials: M
authors.lastname: Millecamps
authors.forename: Andre
authors.initials: A
authors.lastname: Laferrière
authors.forename: Vaigunda J
authors.initials: VJ
authors.lastname: Ragavendran
authors.forename: Laura S
authors.initials: LS
authors.lastname: Stone
authors.forename: Terence J
authors.initials: TJ
authors.lastname: Coderre
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000009:adverse effects; D019333:Endothelin-2 / Q000009:adverse effects; D016232:Endothelins / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D015603:Keratinocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000627:therapeutic use; D017933:Peripheral Nervous System / Q000378:metabolism*; D010812:Physical Stimulation / Q000009:adverse effects; D010880:Piperidines / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000378:metabolism*; D012019:Reflex Sympathetic Dystrophy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019333:Endothelin-2; D016232:Endothelins; D009292:Narcotic Antagonists; D009842:Oligopeptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D010880:Piperidines; D017466:Receptors, Endothelin; C074308:sovateltide; D009270:Naloxone; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)