OTR-MOR异源二聚体在吗啡耐受中的作用及其机制

Morphine was the representative potent analgesic drug of the opioids, and widely used in clinical treatment of various types of acute and chronic pain, especially for advanced cancer patients. However, the application with morphine for long-term could cause morphine tolerance, and morphine tolerance might be related to morphine dependence.The mechanism of morphine tolerance was complex, and a variety of factors were related. Among them the opioid receptor dimerization mechanism was particularly concerned. Although the opioid receptor dimerization had been reported, the opioid receptor subtypes heterologous dimerization had not been reported. Our previous studies showed that oxytocin (OT) could cause obvious analgesic effect independent of the endogenous opioid system, and could enhance the analgesic effect of morphine and against the morphine tolerance. We first found that OT receptors and opioid receptor subtypes (MOR) could form a heterologous dimer, and bifunctional ligands could against the morphine tolerance with spinal intrathecal injection. As OT and morphine coprocessing could promote MOR internalization, it suggested that the inhibition of morphine tolerance with the bifunctional ligand treatment might be related to the internalization of MOR. Therefore, this study will further define the role of OTR-MOR heterologous dimers in morphine tolerance, and investigated the molecular mechanism of against the morphine tolerance of OT via OTR-MOR heterologous dimers by using IP, BiFC, cell membrane molecule fluorescence labeling and immunohistochemical and molecular and cellular biology technology with the bifunctional ligand (endomorphine- (GS4) 3-OT) design by ourselves, and to provide theoretical and experimental basis for designing and developing the new effective drugs for the treatment of morphine tolerance.

长期应用吗啡可引起吗啡耐受，而吗啡耐受又与吗啡依赖有关。吗啡耐受机制复杂，与多种因素有关，其中阿片受体二聚化机制尤为关注，虽然阿片受体亚型二聚体有报道，但与阿片受体亚型异源二聚化尚未见报道。我们以往研究表明，催产素（OT）可不依赖内源性阿片系统产生明显镇痛效应、增强吗啡镇痛及对抗吗啡耐受作用；并首次发现OT受体与阿片受体亚型（MOR）可形成异源二聚体；而且髓鞘内注射双功能配体可对抗吗啡耐受，由于OT和吗啡共处理可促进MOR内化，提示这种双功能配体抑制吗啡耐受可能与其诱导的MOR内化有关。因此，本研究将进一步明确OTR-MOR异源二聚体在吗啡耐受中的作用，并通过自行设计的双功能配体,采用IP、BiFC、细胞膜上分子荧光标记和免疫组化等分子和细胞生物学技术，探讨OT通过OTR-MOR异源二聚体对抗吗啡耐受作用的分子机制，为开发和设计有效治疗吗啡耐受的新药物提供理论基础和实验依据。