Narita M, Suzuki T, Misawa M, Nagase H, Nabeshima A, Ashizawa T, Ozawa H, Saito T, Takahata N
Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan.
Brain Res. 1992 Nov 20;596(1-2):209-14. doi: 10.1016/0006-8993(92)91549-t.
Glibenclamide is one of the most potent sulfonylurea-derived antidiabetic drugs which block the adenosine triphosphate-sensitive potassium (KATP) channels. In the present study, we found that none of morphine, U-50,488H (a selective kappa agonist) and baclofen (a selective GABAB agonist) added to the incubation medium at concentrations up to 10(-4) M had appreciable effect on the specific binding of [cyclohexyl-2,3-3H(N)]glibenclamide ([3H]glibenclamide) to the isolated mouse brain microsomes. The analgesic activity induced by intracerebroventricular injection (i.c.v.) of morphine but not U-50,488H was antagonized by pretreatment with either i.c.v. glibenclamide or beta-funaltrexamine (beta-FNA; a selective mu antagonist) in mice. Furthermore, the increasing effect of i.c.v. morphine on the spinal noradrenaline (NA) turnover was greatly antagonized by i.c.v. pretreatment with either beta-FNA or glibenclamide. From these results, we demonstrated that KATP channels play an important role as indirect modulators of the supraspinal analgesia induced by mu agonist but not kappa agonist in mice, and the activation of descending noradrenergic system induced by i.c.v. morphine appears to be suppressed by the blockade of KATP channels.
格列本脲是最有效的磺酰脲类抗糖尿病药物之一，它能阻断三磷酸腺苷敏感性钾（KATP）通道。在本研究中，我们发现，在孵育培养基中添加浓度高达10⁻⁴ M的吗啡、U - 50,488H（一种选择性κ激动剂）和巴氯芬（一种选择性GABAB激动剂），对[环己基 - 2,3 - ³H(N)]格列本脲（[³H]格列本脲）与分离的小鼠脑微粒体的特异性结合均无明显影响。在小鼠中，脑室内注射（i.c.v.）吗啡而非U - 50,488H诱导的镇痛活性，可被i.c.v.格列本脲或β - 氟纳曲酮（β - FNA；一种选择性μ拮抗剂）预处理所拮抗。此外，i.c.v.吗啡对脊髓去甲肾上腺素（NA）周转的增强作用，可被i.c.v.β - FNA或格列本脲预处理大大拮抗。从这些结果来看，我们证明KATP通道作为间接调节小鼠中由μ激动剂而非κ激动剂诱导的脊髓上镇痛的调节剂发挥重要作用，并且i.c.v.吗啡诱导的下行去甲肾上腺素能系统的激活似乎被KATP通道的阻断所抑制。
