Kappa-opioid receptor-mediated antinociception in the rat. I. Comparative actions of mu- and kappa-opioids against noxious thermal, pressure and electrical stimuli.

This study examined the comparative efficacy of mu- and kappa-opioids in modulating the tail-withdrawal response to matched intensity heat and pressure stimuli and the vocalization response to electrical stimulation in the rat. All drugs were given s.c. The mu-agonists, morphine and fentanyl, were equipotent against heat and pressure at all intensities. The kappa-agonists, U50,488H and U69,593 also acted against pressure in an intensity-independent fashion. However, their action against heat was intensity-dependent being greatest against "low" and least against "high" intensity. At "moderate" intensities, morphine, fentanyl, U69,593, U50,488H and 2 other kappa-agonists (bremazocine and tifluadom) were equipotent against heat and pressure. The action of tifluadom was stereospecific. Naltrexone (a preferential mu-antagonist) was 10 times more potent in blocking the actions of morphine and fentanyl (as compared to U69,593 and U50,488H) against both heat and pressure. The preferential kappa-antagonists, nor-binaltorphimine and MR 2266, were 5- and 2-fold, respectively, more potent against the kappa-ligands for both heat and pressure. The antagonism of MR 2266 was expressed stereospecifically. Fentanyl and morphine induced a powerful antinociception against electrical stimulation whereas U69,593, U50,488H, bremazocine and tifluadom were completely inactive. Thus, kappa-opioid receptors can mediate antinociception against noxious thermal stimuli. However, in contrast to mu-receptors, this antinociception against heat is intensity-dependent. Kappa-agonists, in distinction to mu-agonists, are inactive against electrical stimulation.