MrgC受体调控慢性吗啡诱发神经胶质细胞激活的研究

Mas-related gene C receptors (MrgC) are uniquely distributed in the small-sized neurons of trigeminal and dorsal root ganglia and belong to G protein-coupled receptors. It has been demonstrated that the activation of MrgC receptors can inhibit tolerance to morphine-induced analgesia. Our pilot experiment shows that the effect of MrgC receptors on morphine tolerance may be ascribed to the inhibition of glial activation in the spinal cord. This application proposes to study the effects of MrgC receptors on glial cells in the spinal dorsal horn and dorsal root ganglia. The study aims to investigate the possible involvement of MrgC receptors in the development of morphine tolerance and it's modulation on the chronic morphine-induced glial activation. We will examine the hypothesis that MrgC receptors can inhibit the synthesis and release of the excitatory neurotransmitter and neuromodulator in the DRG neurons, preventing cross-talk between DRG neurons and spinal microglia or DRG satellite cells. This study will explore neurobiological mechanisms of modulation of morphine tolerance by MrgC receptors and the principle of the development of morphine tolerance as well. As MrgC receptors are highly restricted in pain-related neurons in sensory ganglia, targeting these receptors will not impact other physiological functions. Hence, the present study will also provide evidence to support that MrgC receptors can be considered as a therapeutic target of relieving morphine tolerance in clinic.

MrgC受体独特性地分布在感觉神经节小细胞神经元中，属G蛋白偶联受体；其激活能抑制吗啡镇痛作用耐受。过去的研究和预实验提示，这一作用可能与MrgC受体抑制脊髓胶质细胞的活动有关。本项目拟研究MrgC受体对脊髓背角和背根神经节(DRG)中胶质细胞的作用。目的在于：探讨MrgC受体是否参与吗啡耐受的发生；MrgC受体如何调控慢性应用吗啡引起的胶质细胞激活；验证假说，即MrgC受体抑制DRG神经元兴奋性递质和调质的合成和释放，从而调控神经元和脊髓小胶质细胞、和DRG卫星细胞(属胶质细胞)之间的cross-talk。本项目主要研究MrgC受体抑制吗啡耐受的神经生物学机制，也将涉及对吗啡耐受形成机理的探讨。MrgC受体的分布具高度特异性，如以其为靶点，产生的副作用会很小或没有。故本研究结果还可能为MrgC受体作为临床上治疗吗啡耐受的药物靶点奠定理论基础。

MrgC受体独特性地只分布在感觉神经节小细胞神经元中，在其它全身所有其它组织中都不存在。属G蛋白偶联受体；其激活能抑制吗啡镇痛作用耐受。本项目探讨了MrgC受体对脊髓背角和背根神经节(DRG)中胶质细胞的作用及其神经生物学机制。研究结果显示，激活MrgC受体，能抑制慢性应用吗啡引起的脊髓背角小胶质细胞和星型胶质细胞的激活，抑制胶质细胞的功能增强，即抑制脊髓背角P2X4和白介素-1β。MrgC受体也能抑制慢性吗啡诱发的DRG卫星胶质细胞的激活。这些胶质细胞抑制的机制是：MrgC受体能抑制慢性应用吗啡引起的脊髓背角CGRP释放、DRG中MMP-9、白介素-1β、fractalkine与TLR4的表达。从而提出，MrgC受体抑制DRG神经元兴奋性递质和调质的合成和释放，从而调控神经元和脊髓小胶质细胞、和DRG卫星细胞(属胶质细胞)之间的相互影响，是其抑制吗啡耐受的神经学机制。这些研究为将MrgC受体作为临床上抑制吗啡耐受的药理学靶点奠定了理论基础。