Codd E E, Shank R P, Schupsky J J, Raffa R B
R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania, USA.
J Pharmacol Exp Ther. 1995 Sep;274(3):1263-70.
Although it is well established that the analgesic effects of morphine are mediated by opioid receptors, previous studies have shown that some opioids additionally inhibit the uptake of serotonin and norepinephrine. The present investigation of a diverse group of opioids revealed that structurally identifiable subgroups inhibited the neuronal reuptake of these monoamines. Phenanthrene opioids with an oxygen bridge between C4 and C5, such as morphine and naloxone (group I), did not block norepinephrine or serotonin uptake, whereas phenanthrene opioids without the oxygen bridge and the C6-OH moiety, such as levorphanol and levomethorphan (group II), did inhibit uptake, as did nonphenanthrene opioids, such as d-propoxyphene and methadone (group III). Affinity at the mu opioid receptor correlated with antinociceptive potency (r = 0.87, P < .05). Although the antinociceptive activity of the "active enantiomers" of group II and III compounds also correlated with their affinity at the mu opioid receptor (r = 0.85, P = .007), additional consideration of serotonin uptake inhibiting activity (but not of norepinephrine uptake inhibiting activity) significantly improved the correlation between antinociceptive potency and the in vitro activity of these compounds (r = 0.915, P = .0017). Additionally, for group II and III (but not group I) compounds, smaller differences between enantiomers in antinociceptive potency than in mu receptor affinity were noted, presumably because of the contribution of uptake inhibition to the antinociceptive activity of group II and III compounds. Evidence also is provided suggesting a broader role for the combination of mu opioid affinity and 5-hydroxytryptamine uptake inhibition in the activity of other antinociceptive agents.
虽然吗啡的镇痛作用是由阿片受体介导的这一点已得到充分证实，但先前的研究表明，一些阿片类药物还能额外抑制血清素和去甲肾上腺素的摄取。目前对一组不同阿片类药物的研究表明，结构上可识别的亚组会抑制这些单胺类物质的神经元再摄取。在C4和C5之间有一个氧桥的菲类阿片类药物，如吗啡和纳洛酮（第一组），不会阻断去甲肾上腺素或血清素的摄取，而没有氧桥和C6 - OH基团的菲类阿片类药物，如左啡诺和左美沙芬（第二组），确实会抑制摄取，非菲类阿片类药物，如右旋丙氧芬和美沙酮（第三组）也是如此。对μ阿片受体的亲和力与抗伤害感受效能相关（r = 0.87，P <.05）。虽然第二组和第三组化合物的“活性对映体”的抗伤害感受活性也与其对μ阿片受体的亲和力相关（r = 0.85，P =.007），但额外考虑血清素摄取抑制活性（而非去甲肾上腺素摄取抑制活性）显著改善了这些化合物的抗伤害感受效能与体外活性之间的相关性（r = 0.915，P =.0017）。此外，对于第二组和第三组（而非第一组）化合物，观察到对映体之间在抗伤害感受效能上的差异小于在μ受体亲和力上的差异，推测这是由于摄取抑制对第二组和第三组化合物抗伤害感受活性的贡献。还提供了证据表明，μ阿片亲和力和5 - 羟色胺摄取抑制的组合在其他抗伤害感受剂的活性中具有更广泛的作用。
