DIFFERENTIAL ANTAGONISM OF BREMAZOCINE-INDUCED AND U69,593-INDUCED ANTINOCICEPTION BY QUADAZOCINE - FURTHER FUNCTIONAL EVIDENCE OF OPIOD KAPPA-RECEPTOR MULTIPLICITY IN THE MOUSE

In these studies, the antagonistic actions of methyl-2,6-methano-3-ben zazocin-11-yl)-3-pentanone methanesulfonate (quadazocine) were evaluat ed against the kappa-receptor-mediated antinociceptive effects of i.c. v. rolidinylyl-oxaspiro(4,5)dec-8-yl)benzeneacetamide (U69,593) or bre mazocine 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 f ashion, supporting previous suggestions of differences in kappa recept ors mediating the antinociceptive effects of these agonists. Quadazoci ne, however, also antagonized the antinociceptive effects of both DAMG O (opioid mu agonist) and DPDPE (opioid delta agonist) at doses approx imately 3-fold less than those needed to attenuate significantly the e ffects of bremazocine. The structurally diverse kappa opioids lidinyl) -cyclohexyl]benzo[b]-thiophene-4-acetamide (PD 117,302), ethylketocycl azocine (EKC) and tifluadom were studied under kappa-selective conditi ons, and the sensitivity of their effects to ro-N-[2(1-pyrrolidinyl)cy clohexyl]benzeneacetamide [(-)-UPHIT] (kappa1 antagonist) or quadazoci ne (kappa2 antagonist) was determined. On this basis PD 117,302, EKC a nd tifluadom were classified as acting at opioid kappa1, kappa1, and k appa2 receptors, respectively; EKC and tifluadom were also shown to ha ve significant activity at opioid mu, but not delta, receptors. These data demonstrating two-way differential antagonism of U69,593 and brem azocine by quadazocine and (-)-UPHIT provide strong functional evidenc e of opioid kappa receptor subtypes mediating supraspinal antinocicept ion in the mouse. Additionally, the kappa-subtype classification of ka ppa agonists of different structures begins to provide a basis for str ucture-activity relationships of opioids acting at kappa1 and kappa2 r eceptors.