ATP门控钾离子通道开放剂增强阿片类药物的镇痛作用：内源性阿片肽释放的间接证据。

Lohmann A B, Welch S P

Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA 23298-0613, USA.

Eur J Pharmacol. 1999 Dec 3;385(2-3):119-27. doi: 10.1016/s0014-2999(99)00618-4.

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 Ca(2+) 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 ¿ED(50) 44 microg/mouse [95% confidence limits (CLs) from 28 to 68 microg/mouse] for diazoxide¿. Glyburide (10 microg/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 microg/mouse) shifted morphine's dose-response curve 47-fold, while levcromakalim (0.1 microg/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.

ATP 门控钾通道开放剂——二氮嗪、左芬卡尼和吗啡——通过打开 ATP 门控钾通道增强钾离子外流，从而诱导细胞超极化。超极化降低细胞内钙离子水平，导致神经递质释放减少，这有助于这些药物的镇痛作用。先前的研究结果表明内源性阿片类物质的释放是 ATP 门控钾通道开放剂镇痛作用的介导因素。经脑室内（i.c.v.）注射二氮嗪和左芬卡尼，采用甩尾法测定，它们产生了剂量依赖性的镇痛作用——二氮嗪的半数有效剂量（ED50）为 44μg/小鼠[95%置信区间（CLs）为 28 至 68μg/小鼠]。格列本脲（10μg/小鼠），一种 ATP 门控钾通道拮抗剂，减弱了二氮嗪、左芬卡尼和吗啡的作用。二氮嗪和左芬卡尼诱导的镇痛作用均被μ阿片受体选择性拮抗剂 CTOP（D-苯丙氨酸-半胱氨酸-酪氨酸-D-色氨酸-鸟氨酸-苏氨酸-苯丙氨酸-苏氨酸酰胺）和δ阿片受体拮抗剂 ICI 174,864（N，N-二烯丙基-酪氨酸-丙氨酸-丙氨酸-苯丙氨酸-亮氨酸）拮抗，但被κ阿片受体拮抗剂 nor-Binaltorphimine 不同程度地减弱。无活性剂量的钾通道开放剂与阿片受体激动剂的组合产生了显著的镇痛增强作用。二氮嗪（2μg/小鼠）使吗啡的剂量-反应曲线右移 47 倍，而左芬卡尼（0.1μg/小鼠）使曲线右移 27 倍。κ阿片受体激动剂 U50,488H（反式-(+/-)-3,4-二氯-N-[2-(1-吡咯烷基)-环己基]苯乙酰胺甲磺酸盐）的剂量-反应曲线被二氮嗪以平行方式右移 106 倍，而左芬卡尼给药使 U50,488H 的效力增加了 15 倍。二氮嗪使δ阿片受体激动剂 DPDPE[（D-青霉胺(2,5)）-脑啡肽]的剂量-反应曲线非平行左移，而 DPDPE 与左芬卡尼联合时效力增强 6 倍。我们推测内源性阿片类物质介导了 ATP 门控钾通道开放剂诱导的镇痛作用以及阿片类药物的增强作用。