Welch S P, Dunlow L D
Department of Pharmacology & Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond.
J Pharmacol Exp Ther. 1993 Oct;267(1):390-9.
The potassium channel openers could share a common mechanism of action with the opiates in the production of antinociception because both classes of drugs have been shown to enhance potassium efflux. The i.t. administration of the potassium channel openers diazoxide, minoxidil, and lemakalim (BRL38227) produced antinociception as measured in the tail-flick test. The ED50's were 122, 184 and 35 micrograms/mouse, respectively. Minoxidil and lemakalim (BRL 38227) were full agonists, whereas diazoxide was a partial agonist. Diazoxide-induced antinociception was blocked by the potassium channel blockers glyburide, apamin and charybdotoxin. Minoxidil- and lemakalim (i.t.)-induced antinociception was blocked totally by only glyburide. The antinociception produced by the potassium channel openers (i.t.) was blocked differentially by opiate antagonists (i.t.). The antinociceptive effects of diazoxide were blocked by nor binaltorphimine, ICI 174,864 and naloxone. Minoxidil- and lemakalim-induced antinociception was blocked by naloxone and ICI 174,864, but not by nor-binaltorphimine. Naloxone (s.c.) shifted the dose-effect curve for minoxidil to the right in a parallel manner. Morphine-induced antinociception was partially blocked by glyburide and apamin, whereas that produced by DPDPE was blocked totally by apamin. U50, 488H-induced antinociception was blocked partially by apamin. The potassium channel openers (i.t.) were not cross tolerant to morphine when measured in the tail-flick test. Apamin and glyburide precipitated "withdrawal-like" symptoms in morphine-tolerant mice. The interaction of potassium channel openers and opioids probably does not represent a direct interaction of these two classes of drugs at a similar receptor, but rather may occur via an interaction with a common second messenger system such as calcium.
钾通道开放剂在产生抗伤害感受方面可能与阿片类药物具有共同的作用机制，因为这两类药物均已被证明可增强钾离子外流。腹腔注射钾通道开放剂二氮嗪、米诺地尔和雷马卡林（BRL38227）可产生抗伤害感受，这在甩尾试验中得到了测量。其半数有效剂量（ED50）分别为122、184和35微克/只小鼠。米诺地尔和雷马卡林（BRL 38227）是完全激动剂，而二氮嗪是部分激动剂。二氮嗪诱导的抗伤害感受被钾通道阻滞剂格列本脲、蜂毒明肽和蝎毒素阻断。米诺地尔和雷马卡林（腹腔注射）诱导的抗伤害感受仅被格列本脲完全阻断。钾通道开放剂（腹腔注射）产生的抗伤害感受被阿片类拮抗剂（腹腔注射）不同程度地阻断。二氮嗪的抗伤害感受作用被去甲二丙诺啡、ICI 174,864和纳洛酮阻断。米诺地尔和雷马卡林诱导的抗伤害感受被纳洛酮和ICI 174,864阻断，但未被去甲二丙诺啡阻断。纳洛酮（皮下注射）使米诺地尔的剂量效应曲线平行右移。吗啡诱导的抗伤害感受被格列本脲和蜂毒明肽部分阻断，而DPDPE产生的抗伤害感受被蜂毒明肽完全阻断。U50,488H诱导的抗伤害感受被蜂毒明肽部分阻断。在甩尾试验中测量时，钾通道开放剂（腹腔注射）与吗啡不存在交叉耐受性。蜂毒明肽和格列本脲在吗啡耐受小鼠中引发“戒断样”症状。钾通道开放剂与阿片类药物之间的相互作用可能并不代表这两类药物在相似受体上的直接相互作用，而更可能是通过与共同的第二信使系统（如钙）相互作用而发生。
