title: Ultra-long antagonism of kappa opioid agonist-induced diuresis by intracisternal nor-binaltorphimine in monkeys.
abstract: Kappa opioid receptor (KOR) agonists such as U-50488H and bremazocine are analgesics and diuretics. In monkeys, the selective KOR antagonist, nor-binaltorphimine (nor-BNI), produces a long-lasting antagonism of the antinociceptive effects of U-50488H but not those of bremazocine, suggesting that KOR-mediated antinociception may occur through two distinct KORs. The aim of this study was to characterize the antagonist effect of nor-BNI against the diuretic effects of U-50488H and bremazocine in monkeys. Urine outputs were collected over 3 h subsequent to i.m. administration of KOR agonists. Both U-50488H (0.032-1 mg/kg) and bremazocine (0.00032-0.01 mg/kg) dose-dependently increased urine output and the diuretic effect reached a plateau at higher doses. The maximum effect of either U-50488H or bremazocine was approximately 15 ml/kg/3 h of urine. Pretreatment with intracisternal nor-BNI 0.32 mg significantly blocked both U-50488H (0.18 mg/kg)- and bremazocine (0.0032 mg/kg)-induced diuresis for 20 weeks. However, the same dose of nor-BNI 0.32 mg given subcutaneously was not effective. These results demonstrate that central KOR mediate KOR agonist-induced diuresis in monkeys. More important, this study provides functional evidence for a homogenous population of KOR underlying KOR-mediated diuresis and illustrates a unique pharmacological profile of nor-BNI-induced ultra-long KOR antagonism in vivo.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. mko@umich.edu
authors.forename: M C H
authors.initials: MC
authors.lastname: Ko
authors.forename: K J
authors.initials: KJ
authors.lastname: Willmont
authors.forename: H
authors.initials: H
authors.lastname: Lee
authors.forename: G S
authors.initials: GS
authors.lastname: Flory
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 / Q000494:pharmacology; D000818:Animals; D001575:Benzomorphans / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects*; D005260:Female; D007276:Injections, Intraventricular; D008253:Macaca mulatta; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D009292:Narcotic Antagonists / Q000008:administration & dosage*; D017473:Receptors, Opioid, kappa / Q000819:agonists*
chemical_list: D001575:Benzomorphans; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C027248:bremazocine