title: Kappa opioid antagonist effects of systemically administered nor-binaltorphimine in a thermal antinociception assay in rhesus monkeys.
abstract: The effects of subcutaneously administered nor-binaltorphimine (nor-BNI; 1.0 and 3.2 mg/kg) were examined in the warm-water (50 degrees C and 55 degrees C) tail-withdrawal assay in rhesus monkeys (n = 3). Nor-BNI alone produced variable antinociceptive effects in 50 degrees C water up to 3.5 hr after administration but was completely ineffective against the 55 degrees C stimulus. Pretreatment with nor-BNI under conditions where it was devoid of antinociceptive effects produced rightward shifts in dose-effect curves for the kappa opioid agonist U50,488 for as long as 14 and 21 days after 1.0 and 3.2 mg/kg of nor-BNI, respectively. Under conditions when U50,488 dose-effect curves were shifted, nor-BNI (3.2 mg/kg) also caused rightward shifts in the antinociceptive dose-effect curves of the kappa agonist U69,593 but not in those of the mu agonist alfentanil or the kappa agonists [5R-(5,7,8,beta)]N-methyl-N-[7- (1-pirrolidinyl)1-oxaspiro[4,5]dec-8-yl]4-benzofuranaceta mide, bremazocine, ethylketocyclazocine and Mr2033. It is concluded that under the present conditions, nor-BNI acts as a selective kappa opioid antagonist with an extremely long duration of action. These findings are also consistent with the notion that nor-BNI may antagonize only compounds acting at a subtype of kappa opioid receptor.
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor.
authors.forename: E R
authors.initials: ER
authors.lastname: Butelman
authors.forename: S S
authors.initials: SS
authors.lastname: Negus
authors.forename: Y
authors.initials: Y
authors.lastname: Ai
authors.forename: B R
authors.initials: BR
authors.lastname: de Costa
authors.forename: J H
authors.initials: JH
authors.lastname: Woods
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000081:Acetamides / Q000037:antagonists & inhibitors; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001575:Benzomorphans / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D006361:Heating; D008253:Macaca mulatta / Q000502:physiology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000145:classification / Q000502:physiology; D013997:Time Factors
chemical_list: D000081:Acetamides; D000700:Analgesics; D001575:Benzomorphans; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer