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Opioid receptors play an important role in mediating the spinal analgesia. The μ-opioid receptor (MOR) is the major target of opioid drugs widely used in clinics. However, the regulatory mechanisms of analgesic effect and tolerance for clinical MOR-targeting opioids remain to be fully investigated. Previous studies showed the interaction of δ-opioid receptor (DOR) with MOR to form the MOR/DOR heteromers that could be processed in the degradation pathway after DOR agonist treatment. Here we showed that clinical MOR-targeting opioids, morphine, fentanyl and methadone, but not tramadol, caused MOR co-internalization with DORs in both transfected human embryonic kidney 293 cells and primary sensory neurons. Prolonged treatment of morphine led to MOR co-degradation with DORs. Furthermore, fentanyl and methadone, but not tramadol, induced the drug tolerance similar to morphine. Thus, the clinical MOR-targeting opioids including morphine, fentanyl and methadone induce MOR co-internalization with DORs, which may be involved in the analgesic tolerance of these opioids.

Clinical opioids differentially induce co-internalization of μ- and δ-opioid receptors