Reche I, Ruiz-Gayo M, Fuentes J A
Departamento de Farmacologia, Facultad de Farmacia, Universidad Complutense de Madrid, Ciudad Universitaria, Spain.
Neuropharmacology. 1998;37(2):215-22. doi: 10.1016/s0028-3908(98)00005-7.
Delta9-tetrahydrocannabinol (delta9-THC) elicits antinociception in rodents through the central CB1 cannabinoid receptor subtype. In addition. Delta9-THC stimulates the release of dynorphin-related peptides leading to kappa-opioid spinal antinociception. In this work we describe the effect of a mixture of thiorphan (a neutral endopeptidase EC3.4.24.11 inhibitor) and bestatin (an aminopeptidase inhibitor), administered i.c.v., on the antinociceptive effect of peripherally administered delta9-THC in mice. As in the case of morphine or DAMGO ([D-Ala2.N-Me-Phe4,Gly-ol]enkephalin), a mu-selective opioid receptor agonist, the mixture of enkephalin-degrading enzyme inhibitors also enhanced the antinociceptive effect of delta9-THC. This effect was blocked by the CB1 cannabinoid receptor antagonist, SR-141,716-A, as well as by naloxone. The kappa-opioid receptor antagonist nor-binaltorphimine, administered i.t., also antagonized the effect of this combination. Similar results were obtained with the mu-opioid receptor antagonist beta-funaltrexamine after i.c.v. administration. These results demonstrate the involvement of both mu-opioid supraspinal and kappa-opioid spinal receptors in the interaction of both opioid and cannabinoid systems regulating nociception in mice.
Δ9-四氢大麻酚（Δ9-THC）通过中枢CB1大麻素受体亚型在啮齿动物中引发抗伤害感受。此外，Δ9-THC刺激强啡肽相关肽的释放，导致κ-阿片受体脊髓抗伤害感受。在这项工作中，我们描述了脑室内注射硫喷妥（一种中性内肽酶EC3.4.24.11抑制剂）和贝抑素（一种氨肽酶抑制剂）的混合物对小鼠外周给予Δ9-THC的抗伤害感受作用的影响。与吗啡或DAMGO（[D-Ala2，N-Me-Phe4，Gly-ol]脑啡肽）（一种μ-选择性阿片受体激动剂）的情况一样，脑啡肽降解酶抑制剂的混合物也增强了Δ9-THC的抗伤害感受作用。这种作用被CB1大麻素受体拮抗剂SR-141,716-A以及纳洛酮阻断。鞘内注射κ-阿片受体拮抗剂诺-宾丙吗啡也拮抗了这种组合的作用。脑室内注射μ-阿片受体拮抗剂β-芬太尼后也获得了类似的结果。这些结果表明，μ-阿片受体脊髓上和κ-阿片受体脊髓受体都参与了调节小鼠伤害感受的阿片和大麻素系统的相互作用。
