内源性褪黑素能系统参与吗啡耐受的机制研究

Morphine-induced tolerance significantly limits its clinical use in relieving acute and chronic pain. Our pilot studies demonstrate that exogenous melatonin have potential to attenuate morphine tolerance, possibly by inhibiting N-Methyl-D-aspartate (NMDA) receptor activities in the spinal cord. Therefore, down-regulation of melatonergic system in the spinal cord may be play a critical role in the development of morphine tolerance. Using neurons acute morphine tolerance model in vitro and rat chronic morphine tolerance model in vivo, the aim of this project, is to observe the change of melatonergic system in the spinal cord during morphine tolerance and to explain the mechanism of down-regulation of melatonergic system induced by morphine. Meanwhile, we would further certify that the effcts of diferent exogenous melatonergic drugs to prevent morphine tolerance. Because of short of the effective therapy currently, the research with regarding to the regulatory mechanism of melatonergic system becomes most important for us to prevent the development of morphine tolerance. This project provides a theoretical and experimental basis for further understanding morphine tolerance pathogenesis and pathological processes, so as for the development of the potential drugs and treatment, which may result in significant prevention of the morphine tolerance.

吗啡耐受极大限制了其安全、有效用于急慢性疼痛的治疗。我们前期的研究发现：外源性褪黑素通过下调脊髓NMDA受体而预防吗啡耐受。因此，内源性褪黑素的下调可能是吗啡耐受的重要原因。本项目拟采用离体细胞急性吗啡耐受和在体大鼠慢性吗啡耐受的模型，研究吗啡耐受时脊髓内源性褪黑素能系统的改变，并揭示吗啡影响其变化的机制，以及外源性褪黑素能药物对吗啡耐受的影响。吗啡耐受缺乏有效的预防手段，探索内源性褪黑素能系统参与吗啡耐受的机制，为寻找有效预防吗啡耐受的药物和治疗手段提供了理论和实验依据。

我们通过动物实验证实：慢性吗啡鞘内注射可导致大鼠发生吗啡镇痛耐受，同时出现与耐受相关的痛觉过敏。而临床的试验我们也发现：吗啡耐受的癌痛患者相对于吗啡未耐受的癌痛患者痛阈明显下降。通过我们的动物实验发现内源性褪黑素系统参与了吗啡耐受和痛觉敏化发生的机制：吗啡耐受时，血浆中褪黑素水平降低，脊髓背角的μ受体（MOR）表达无变化，褪黑素受体（MT1而不是MT2）表达降低，蛋白激酶C（PKCγ）表达升高。通过该项目一系列的实验我们证实：①内源性褪黑素系统通过血浆褪黑素-MT1-PKCγ通路参与吗啡耐受发生；②外源性的给与褪黑素可以通过该通路抑制吗啡耐受；③内源性褪黑素参与吗啡耐受的机制不依赖MOR；④PKC拮抗剂可以通过抑制PKCγ的激活而抑制吗啡耐受和改善痛觉敏化。.吗啡耐受和痛觉过敏极大限制了吗啡安全、有效用于急慢性疼痛的治疗。且目前吗啡耐受缺乏有效的预防手段，通过本项目一系列的研究发现，为寻找有效预防吗啡耐受的药物和治疗手段提供了理论和实验依据。