Differential antagonism of bremazocine- and U69,593-induced antinociception by quadazocine: Further functional evidence of opioid κ receptor multiplicity in the mouse

P. J. Horan, B. R. De Costa, K. Rice, R. C. Haaseth, Victor J Hruby, Frank Porreca

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In these studies, the antagonistic actions of (-)-1-Cyclopentyl-5- (1,2,3,4,5,-hexahydro-8-hydroxy-3,6,11-trimethyl-2,6-methyano-3-benzazocin- 11-yl)-3-pentanone methanesulfonate (quadazocine) were evaluated against the κ-receptor-mediated antinociceptive effects of i.c.v. (5α,7α,8β)-(+)-N- methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)benzeneacetamide (U69,593) or bremazocine in the mouse warm water tail-flick test. Quadazocine produced no antinociceptive effects alone, and it selectively antagonized the actions of bremazocine, but not U69,593, in a dose- and time-related fashion, supporting previous suggestions of differences in κ receptors mediating the antinociceptive effects of these agonists. Quadazocine, however, also antagonized the antinociceptive effects of both DAMGO (opioid μ agonist) and DPDPE (opioid δ agonist) at doses approximately 3-fold less than those needed to attenuate significantly the effects of bremazocine. The structurally diverse κ opioids (±)-trans-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzo[b]-thiopene-4-acetamide (PD 117,302), ethylketocyclazocine (EKC) and tifluadom were studied under κ-selective conditions, and the sensitivity of their effects to 1S,2S-trans-2-isothiocyanato-4,5-dichloro-N- [2(1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-UPHIT] (κ1 antagonist) or quadazocine (κ2 antagonist) was determined. On this basis PD 117,302, EKC and tifluadom were classified as acting at opioid κ1, κ1, and κ2 receptors, respectively; EKC and tifluadom were also shown to have significant activity at opioid μ, but not δ, receptors. These data demonstrating two-way differential antagonism of U69,593 and bremazocine by quadazocine and (-)-UPHIT provide strong functional evidence of opioid κ receptor subtypes mediating supraspinal antinociception in the mouse. Additionally, the κ-subtype classification of κ agonists of different structures begins to provide a basis for structure-activity relationships of opioids acting at κ1 and κ2 receptors.

Original languageEnglish (US)
Pages (from-to)926-933
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
Publication statusPublished - 1993


ASJC Scopus subject areas

  • Pharmacology

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