Rady J J, Aksu F, Fujimoto J M
Research Service, Medical College of Wisconsin, Milwaukee.
J Pharmacol Exp Ther. 1994 Mar;268(3):1222-31.
Heroin activates delta receptors, whereas morphine activates mu receptors, in the brain of Swiss-Webster mice, to produce antinociception. The present study determined the type of opioid receptor activated by 6-monoacetylmorphine (MAM), a metabolite of heroin. Intracerebroventricular MAM-induced inhibition of the tail-flick response was reduced by coadministration of naltrindole (a delta opioid receptor antagonist), suggesting that i.c.v. MAM, like i.c.v. heroin, acted on delta receptors. This delta receptor-mediated response was not affected by intrathecal (i.t.) administration of yohimbine and methysergide. Thus, the descending noradrenergic and serotonergic neuronal pathways, which are activated by i.c.v. morphine, were not involved in MAM antinociception. In the spinal cord, coadministration of naltrindole with MAM, i.t., decreased antinociception suggesting that MAM acted on spinal delta receptors. This finding is in contrast to i.t. heroin which acts on mu receptors in the spinal cord. These receptor selectivities were also demonstrated for systemically administered MAM and heroin. Thus, i.c.v. naltrindole inhibited both MAM- and heroin-induced antinociception, but i.t. naltrindole only inhibited the MAM response. The following results in ICR mice contrast with those above. Antinociception induced by i.c.v. MAM was decreased by coadministration of naloxone, but not naltrindole, suggesting that MAM, like morphine and heroin, acted on supraspinal mu receptors. Also, this MAM response was inhibited by i.t. administration of methysergide which is consistent with supraspinal mu receptor activation. Furthermore, i.t. MAM acted on spinal mu receptors because i.t. administration of naloxone, but not naltrindole, produced inhibition. In conclusion, the ability to ascribe delta receptor selectivity to the action of heroin and MAM in Swiss-Webster mice served to reinforce the concept that heroin and MAM act primarily on their own and not through formation of morphine. Further elucidation of the difference in heroin and MAM receptor selectivities between Swiss-Webster and ICR mice might contribute to a better understanding of opioid receptor mechanisms.
在瑞士韦伯斯特小鼠脑中，海洛因激活δ受体，而吗啡激活μ受体，从而产生抗伤害感受作用。本研究确定了海洛因的代谢产物6-单乙酰吗啡（MAM）所激活的阿片受体类型。脑室注射MAM诱导的甩尾反应抑制作用，在与纳曲吲哚（一种δ阿片受体拮抗剂）共同给药时减弱，这表明脑室注射MAM与脑室注射海洛因一样，作用于δ受体。这种由δ受体介导的反应不受鞘内注射育亨宾和甲基麦角新碱的影响。因此，由脑室注射吗啡激活的下行去甲肾上腺素能和5-羟色胺能神经通路，不参与MAM的抗伤害感受作用。在脊髓中，鞘内注射时，纳曲吲哚与MAM共同给药会降低抗伤害感受作用，这表明MAM作用于脊髓δ受体。这一发现与鞘内注射海洛因不同，海洛因作用于脊髓μ受体。这些受体选择性在全身给药的MAM和海洛因中也得到了证实。因此，脑室注射纳曲吲哚抑制MAM和海洛因诱导的抗伤害感受作用，但鞘内注射纳曲吲哚仅抑制MAM反应。以下在ICR小鼠中的结果与上述结果不同。脑室注射MAM诱导的抗伤害感受作用，在与纳洛酮共同给药时减弱，但与纳曲吲哚共同给药时未减弱，这表明MAM与吗啡和海洛因一样，作用于脊髓上的μ受体。此外，这种MAM反应受到鞘内注射甲基麦角新碱的抑制，这与脊髓上μ受体的激活一致。此外，鞘内注射MAM作用于脊髓μ受体，因为鞘内注射纳洛酮而非纳曲吲哚会产生抑制作用。总之，在瑞士韦伯斯特小鼠中，将δ受体选择性归因于海洛因和MAM作用的能力，强化了海洛因和MAM主要通过自身作用而非通过吗啡形成起作用的概念。进一步阐明瑞士韦伯斯特小鼠和ICR小鼠之间海洛因和MAM受体选择性的差异，可能有助于更好地理解阿片受体机制。
