Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, Minnesota 55455, United States; Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
ACS Chem Neurosci. 2012 Sep 19;3(9):720-7. doi: 10.1021/cn300049m. Epub 2012 Jul 5.
Morphine and related drugs are widely employed as analgesics despite the side effects associated with their use. Although morphine is thought to mediate analgesia through mu opioid receptors, delta opioid receptors have been implicated in mediating some side effects such as tolerance and dependence. Here we present evidence in rhesus monkeys that morphine, fentanyl, and possibly methadone selectively activate mu-delta heteromers to produce antinociception that is potently antagonized by the delta opioid receptor antagonist, naltrindole (NTI). Studies with HEK293 cells expressing mu-delta heteromeric opioid receptors exhibit a similar antagonism profile of receptor activation in the presence of NTI. In mice, morphine was potently inhibited by naltrindole when administered intrathecally, but not intracerebroventricularly, suggesting the possible involvement of mu-delta heteromers in the spinal cord of rodents. Taken together, these results strongly suggest that, in primates, mu-delta heteromers are allosterically coupled and mediate the antinociceptive effects of three clinically employed opioid analgesics that have been traditionally viewed as mu-selective. Given the known involvement of delta receptors in morphine tolerance and dependence, our results implicate mu-delta heteromers in mediating both antinociception and these side effects in primates. These results open the door for further investigation in humans.
吗啡和相关药物被广泛用作镇痛药，尽管它们的使用与副作用有关。虽然吗啡被认为通过μ阿片受体介导镇痛作用，但δ阿片受体已被牵连到介导一些副作用，如耐受和依赖。在这里，我们在恒河猴中提供了证据，表明吗啡、芬太尼和可能的美沙酮选择性地激活μ-δ杂合体以产生镇痛作用，这种作用被δ阿片受体拮抗剂纳曲吲哚（NTI）强烈拮抗。在表达μ-δ杂合阿片受体的 HEK293 细胞中的研究显示，在存在 NTI 的情况下，受体激活具有相似的拮抗作用谱。在小鼠中，吗啡鞘内给药时被纳曲吲哚强烈抑制，但脑室内给药时不被抑制，这表明μ-δ杂合体可能参与啮齿动物的脊髓。综上所述，这些结果强烈表明，在灵长类动物中，μ-δ杂合体是变构偶联的，并介导三种临床上使用的阿片类镇痛药的镇痛作用，这些药物传统上被认为是μ选择性的。鉴于δ受体在吗啡耐受和依赖中的已知作用，我们的结果表明，μ-δ杂合体在灵长类动物中介导镇痛作用和这些副作用。这些结果为人类的进一步研究开辟了道路。
