1 Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
2 University of Chinese Academy of Sciences, Shanghai, China.
Mol Pain. 2018 Jan-Dec;14:1744806918769492. doi: 10.1177/1744806918769492. Epub 2018 Mar 27.
Opioid receptors play an important role in mediating the spinal analgesia. The μ-opioid receptor is the major target of opioid drugs widely used in clinics. However, the regulatory mechanisms of analgesic effect and tolerance for clinical μ-opioid receptor-targeting opioids remain to be fully investigated. Previous studies showed the interaction of δ-opioid receptor with μ-opioid receptor to form the μ-opioid receptor/δ-opioid receptor heteromers that could be processed in the degradation pathway after δ-opioid receptor agonist treatment. Here, we showed that clinical μ-opioid receptor-targeting opioids, morphine, fentanyl, and methadone, but not tramadol, caused μ-opioid receptor co-internalization with δ-opioid receptors in both transfected human embryonic kidney 293 cells and primary sensory neurons. Prolonged treatment of morphine led to μ-opioid receptor co-degradation with δ-opioid receptors. Furthermore, fentanyl and methadone, but not tramadol, induced the drug tolerance similar to morphine. Thus, the clinical μ-opioid receptor-targeting opioids including morphine, fentanyl, and methadone induce μ-opioid receptor co-internalization with δ-opioid receptors, which may be involved in the analgesic tolerance of these opioids.
阿片受体在介导脊髓镇痛中发挥重要作用。μ 阿片受体是临床上广泛使用的阿片类药物的主要靶点。然而，临床 μ 阿片受体靶向阿片类药物的镇痛效果和耐受的调节机制仍有待充分研究。先前的研究表明，δ 阿片受体与 μ 阿片受体相互作用形成 μ 阿片受体/δ 阿片受体异源二聚体，该异源二聚体可以在 δ 阿片受体激动剂处理后通过降解途径进行加工。在这里，我们表明临床 μ 阿片受体靶向阿片类药物，如吗啡、芬太尼和美沙酮，但不是曲马多，会导致转染的人胚肾 293 细胞和原代感觉神经元中 μ 阿片受体与 δ 阿片受体共内吞。吗啡的长期治疗导致 μ 阿片受体与 δ 阿片受体共降解。此外，芬太尼和美沙酮，但不是曲马多，会诱导类似于吗啡的药物耐受。因此，包括吗啡、芬太尼和美沙酮在内的临床 μ 阿片受体靶向阿片类药物会诱导 μ 阿片受体与 δ 阿片受体共内吞，这可能与这些阿片类药物的镇痛耐受有关。
