ATP-gated K+ channel openers enhance opioid antinociception:: indirect evidence for the release of endogenous opioid peptides

The ATP-gated K+ channel openers - diazoxide, levcromakalim and morphine - enhance K+ efflux by opening ATP-gated K+ channels, thereby inducing cell hyperpolarization. Hyperpolarization decreases intracellular Ca2+ levels, which leads to a decrease in neurotransmitter release contributing to the antinociceptive effects of the drugs. Previous findings implicate the release of endogenous opioids as the mediator of the antinociceptive effects of ATP-gated K+ channel openers. Diazoxide and levcromakalim, administered intracerebroventricularly (i.c.v.), produced dose-dependent antinociception as determined by the tail-flick method {ED50 44 mu g/mouse [95% confidence limits (CLs) from 28 to 68 mu g/mouse] for diazoxide}. Glyburide (10 mu g/mouse), an ATP-gated K+ channel antagonist, attenuated the effects of diazoxide, levcromakalim and morphine. Diazoxide- and levcromakalim-induced antinociception were both antagonized by CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide), a mu-opioid receptor selective antagonist, and ICI 174,864 (N, N-diallyl-Tyr-Aib-Aib-Phe-Leu), a delta-opioid receptor antagonist, but were differentially attenuated by the kappa-opioid receptor antagonist, nor-Binaltorphimine. Combinations of inactive doses of the K+ channel openers and opioid receptor agonists produced significant antinociceptive enhancement. Diazoxide (2 mu g/mouse) shifted morphine's dose-response curve 47-fold, while levcromakalim (0.1 mu g/mouse) shifted the curve 27-fold. The dose-response curve of kappa-opioid receptor agonist U50,488H (trans-(+/-)-3, 4 Dichloro-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane sulfonate) was shifted 106-fold by diazoxide in a parallel manner, while levcromakalim administration increased the potency of U50,488H by 15-fold. Diazoxide shifted the dose-response curve of the delta-opioid receptor agonist, DPDPE [(D-Pen(2,5))-enkephalin], leftward in a non-parallel manner, while DPDPE was 6-fold more potent when combined with levcromakalim. We hypothesize that endogenous opioids mediate ATP-gated K+ channel opener-induced antinociception and enhancement of opioids. (C) 1999 Elsevier Science B.V. All rights reserved.