鞘内吗啡耐受可致大鼠脊髓mGluR5激活，我们前期研究证实抑制或敲除脊髓mGluR5可影响吗啡耐受发生，而调节PLC的活性和PKC的激活可能是其主要机制，同时研究表明耐受致mGluR5激活可上调脊髓内兴奋性/抑制性氨基酸平衡，影响mu受体-G蛋白偶联，进而影响吗啡耐受过程。P2X3R为离子型嘌呤受体，既往研究证实其参与神经病理性痛及炎性痛等慢性痛的调制，与mGluR5有相似的表达区域，主要在DRG及脊髓浅层表达，预实验及既往研究已经证实P2X3R与mGluR5存在广泛的共表达。PIP2水平、胞内钙离子及PKC激活均参与了P2X3R在慢性痛中的调制，而PIP2、Ca2+、PLC及PKC均为mGluR5调节疼痛及耐受通路上的重要靶点，已有研究表明mGluR5可介导P2X3R的激活，在我们前期研究基础上，课题组认为耐受激活的mGluR5可调节P2X3R影响吗啡耐受的发生，并就其详细机制展开研究。

Intrathecal morphine antinociceptive tolerance might result in the activation of spinal metabotropic glutamate receptor 5 (mGluR5) and we showed that morphine antinociceptive tolerance could be attenuated by inhibiting or koncking down of spinal mGluR5. Modulation of PLC activity and activation of PKC might be the key factor in mGluR5-mediated morphine antinociceptive tolerance. We also showed that mGluR5-mediated morphine antinociceptive tolerance could regulate the balance of excitatory/inhibitory G protein and affect the mu receptor-G protein coupling which deteriorate the tolerance. P2X3 receptor is ionotropic purinergic receptor and was shown to participate in and modulate the chronic neuropathic or inflammatory pain. It has a similar distribution as mGluR5 and mainly located in DRG neuron or laminaeⅠ or Ⅱ in the spinal cord. Preliminary experiment and previous studies verified the co-expression of mGluR5 and P2X3 receptor in above involved locations. Studies showed that PIP2, intracellular calcium and PKC modulate the P2X3 receptor in chronic pain. Whereas, PIP2, intracellar calcium, PLC and PKC are all the important target in mGluR5-mediated pain or morphine antinociceptive tolerance modulation. A previous research also showed a metabotropic regulation of ATP-gated P2X3 receptors in their work. Basing on previous work, we suppose that mGluR5 might mediate the activation of P2X3 receptor during the development of morphine antinociceptive tolerance. This project will focus on this mGluR5-mediated P2X3 receptor in morphine-induced antinociceptive tolerance and their detailed mechanisms.