Vonvoigtlander P F, Lewis R A, Neff G L
J Pharmacol Exp Ther. 1984 Nov;231(2):270-4.
The serotonergic dependence of mu and kappa opioid analgesia was compared in the mouse tail-flick and hot-plate assays using morphine and the selective kappa agonist, U-50, 488H, respectively. Depletion of serotonin with p-chlorophenylalanine resulted in a marked antagonism of U-50,488H analgesic potency in both assays, as did reserpine pretreatment. Both of these effects were dose-related and the latter was reversed by treatment with the serotonin precursor, 5-hydroxytryptophan. Several reputed serotonin antagonists (cyproheptadine, ketanserin and pirenperone) also antagonized U-50,488H analgesia. In contrast, the analgesic potency of morphine was only decreased slightly by p-chlorophenylalanine and reserpine, and not at all by the serotonin antagonists. Thus, kappa, but not mu, analgesia is strongly dependent upon serotonergic mechanisms in these assays. However 5-hydroxytryptophan did not enhance U-50,488H analgesia in nonpretreated mice or in mice made tolerant to U-50,488H. Likewise, it did not alter the development of U-50,488H tolerance. On this basis it appears that kappa opioid tolerance is not due to serotonergic hypofunction.
分别使用吗啡和选择性κ激动剂U-50,488H，在小鼠甩尾试验和热板试验中比较了μ和κ阿片类镇痛的5-羟色胺能依赖性。用对氯苯丙氨酸耗竭5-羟色胺导致在两种试验中U-50,488H镇痛效力均出现明显拮抗，利血平预处理也有同样结果。这两种效应均与剂量相关，后者可通过用5-羟色胺前体5-羟色氨酸治疗而逆转。几种著名的5-羟色胺拮抗剂（赛庚啶、酮色林和哌仑西平）也拮抗U-50,488H镇痛作用。相比之下，对氯苯丙氨酸和利血平仅使吗啡的镇痛效力稍有降低，而5-羟色胺拮抗剂则对其毫无影响。因此，在这些试验中，κ而非μ镇痛作用强烈依赖于5-羟色胺能机制。然而，5-羟色氨酸在未预处理的小鼠或对U-50,488H产生耐受性的小鼠中并未增强U-50,488H的镇痛作用。同样，它也未改变U-50,488H耐受性的产生。基于此，似乎κ阿片类耐受性并非由于5-羟色胺能功能减退所致。
