Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu 211166, China.
Sci Rep. 2016 Dec 22;6:38746. doi: 10.1038/srep38746.
Tolerance induced by morphine remains a major unresolved problem and significantly limits its clinical use. Recent evidences have indicated that dopamine D2 receptor (D2DR) is likely to be involved in morphine-induced antinociceptive tolerance. However, its exact effect and molecular mechanism remain unknown. In this study we examined the effect of D2DR on morphine antinociceptive tolerance in mice spinal cord. Chronic morphine treatment significantly increased levels of D2DR in mice spinal dorsal horn. And the immunoreactivity of D2DR was newly expressed in neurons rather than astrocytes or microglia both in vivo and in vitro. Blockade of D2DR with its antagonist (sulpiride and L-741,626, i.t.) attenuated morphine antinociceptive tolerance without affecting basal pain perception. Sulpiride (i.t.) also down-regulated the expression of phosphorylation of NR1, PKC, MAPKs and suppressed the activation of astrocytes and microglia induced by chronic morphine administration. Particularly, D2DR was found to interact with μ opioid receptor (MOR) in neurons, and chronic morphine treatment enhanced the MOR/D2DR interactions. Sulpiride (i.t.) could disrupt the MOR/D2DR interactions and attenuate morphine tolerance, indicating that neuronal D2DR in the spinal cord may be involved in morphine tolerance possibly by interacting with MOR. These results may present new opportunities for the treatment and management of morphine-induced antinociceptive tolerance which often observed in clinic.
吗啡诱导的耐受仍然是一个未解决的主要问题，严重限制了其临床应用。最近的证据表明，多巴胺 D2 受体（D2DR）可能参与吗啡诱导的镇痛耐受。然而，其确切的作用和分子机制尚不清楚。在本研究中，我们研究了 D2DR 对小鼠脊髓中吗啡镇痛耐受的影响。慢性吗啡处理显著增加了小鼠脊髓背角 D2DR 的水平。并且 D2DR 的免疫反应性在体内和体外均新表达于神经元，而不是星形胶质细胞或小胶质细胞。用其拮抗剂（硫必利和 L-741,626，鞘内注射）阻断 D2DR 可减轻吗啡镇痛耐受，而不影响基础痛觉感知。硫必利（鞘内注射）还下调了磷酸化 NR1、PKC、MAPKs 的表达，并抑制了慢性吗啡给药引起的星形胶质细胞和小胶质细胞的激活。特别是，发现 D2DR 在神经元中与μ阿片受体（MOR）相互作用，慢性吗啡处理增强了 MOR/D2DR 相互作用。硫必利（鞘内注射）可破坏 MOR/D2DR 相互作用并减轻吗啡耐受，表明脊髓中的神经元 D2DR 可能通过与 MOR 相互作用参与吗啡耐受。这些结果可能为治疗和管理临床上经常观察到的吗啡诱导的镇痛耐受提供新的机会。
