title: NOP receptor antagonist, JTC-801, blocks cannabinoid-evoked hypothermia in rats.
abstract: The present study used the endpoint of hypothermia to investigate cannabinoid and nociceptin/orphanin FQ (N/OFQ) interactions in conscious animals. Prior work has established that cannabinoids produce hypothermia by activating central cannabinoid CB(1) receptors. The administration of N/OFQ into the brain also causes significant hypothermia. Those data suggest a link between cannabinoid CB(1) receptors and N/OFQ peptide (NOP) receptors in the production of hypothermia. Therefore, we determined if NOP receptor activation is required for cannabinoid-evoked hypothermia and if cannabinoid CB(1) receptor activation is necessary for N/OFQ-induced hypothermia. In actual experiments, a cannabinoid agonist, WIN 55212-2 (2.5, 5, and 10 mg/kg, i.p.), caused significant hypothermia in male Sprague-Dawley rats (200-225 g). A NOP receptor antagonist, JTC-801 (1 mg/kg, i.p.), did not affect body temperature. For combined administration, JTC-801 (1 mg/kg, i.p.) blocked a significant proportion of the hypothermia caused by each dose of WIN 55212-2 (2.5, 5, and 10 mg/kg, i.p.). JTC-801 (1 mg/kg, i.p.) also blocked the hypothermia caused by another cannabinoid agonist, CP-55, 940 (1 mg/kg, i.p.). In separate experiments, the direct administration of N/OFQ (9 microg/rat, i.c.v.) into the brain produced significant hypothermia. The hypothermic effect of N/OFQ was blocked by JTC-801 (1 mg/kg, i.p.) but not by a selective cannabinoid CB(1) antagonist, SR 141716A (5 mg/kg, i.m.). The finding that a NOP receptor antagonist abolishes a significant percentage of cannabinoid-induced hypothermia suggests that NOP receptor activation is required for cannabinoids to produce hypothermia. This interaction, quantitated in the present study, is the first evidence that NOP receptors mediate a cannabinoid-induced effect in conscious animals.
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy and Center for Substance Abuse Research, 3307 North Broad Street, Philadelphia, PA 19140, USA. scott.rawls@temple.edu
authors.forename: Scott M
authors.initials: SM
authors.lastname: Rawls
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Schroeder
authors.forename: Zhe
authors.initials: Z
authors.lastname: Ding
authors.forename: Tony
authors.initials: T
authors.lastname: Rodriguez
authors.forename: Nurulain
authors.initials: N
authors.lastname: Zaveri
mesh_terms: D000634:Aminoquinolines / Q000378:metabolism*; D000700:Analgesics / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000378:metabolism*; D048588:Benzoxazines / Q000378:metabolism; D001831:Body Temperature; D002186:Cannabinoids / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced*; D008297:Male; D009025:Morpholines / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism; D009292:Narcotic Antagonists; D010880:Piperidines / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D000077285:Rimonabant; D000094942:Nociceptin Receptor
chemical_list: D000634:Aminoquinolines; D000700:Analgesics; D001549:Benzamides; D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; C433236:N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide; D009281:Naphthalenes; D009292:Narcotic Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D011957:Receptors, Opioid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant; D000094942:Nociceptin Receptor