嘌呤受体P2X7调制骨癌痛大鼠吗啡镇痛耐受的机制分析

骨癌痛是最严重的慢性痛之一，吗啡仍是最有效的镇痛药。然而，长期应用吗啡会导致镇痛耐受。迄今为止，我们对吗啡耐受机理的认识大都来自于在正常动物长期给予吗啡引起对生理性痛的镇痛耐受研究。然而，临床上遇到的吗啡镇痛耐受问题都发生在慢性痛特别是癌痛患者身上。因此在骨癌痛动物模型上研究吗啡镇痛耐受的发生机制则更具现实意义。.由胶质细胞活化并释放促炎性细胞因子介导的中枢神经炎可能是慢性痛和吗啡镇痛耐受产生和维持的共同机制。本课题首次在骨癌痛模型大鼠，长期给予吗啡治疗，观察其镇痛耐受发生、发展中，嘌呤受体P2X7介导的脊髓小胶质细胞p38/MAPK信号通路激活、促炎性细胞因子（如IL-1β和IL-18）释放、星形胶质细胞激活和产物（如D-Serine）释放以及脊髓感觉神经元兴奋性增强之间的相互作用关系，并通过对这一机制的探讨，寻找对抗吗啡耐受的干预手段，增强阿片镇痛效应。

Bone cancer pain is the most severe chronic pain, and morphine is the most effective analgesic. However, long-term morphine therapy produces morphine antinociceptive tolerance. So far, studies on morphine tolerance are mostly carried out in normal animals, despite that the clinical morphine antinociceptive tolerance occurs only in patients with chronic pain. Actually, chronic pathological pain is quite different from normal physiological pain in mechanisms. Therefore, it is more meaningful to study the mechanisms of morphine tolerance in chronic pain animal models..Neuroinflammation plays an important role in the development of both chronic pain and morphine tolerance. For the first time, we will investigate the role of P2X7 purinoceptor-mediated the activation of spinal microglial p38/MAPK signaling pathway, proinflammatory cytokines (e.g. IL-1β and IL-18) and astrocytic products (e.g. D-Serine) release, and hypersensitivity of spinal dorsal horn neurons in morphine tolerance in a rat model of bone cancer pain. These proposed studies may reveal P2X7R as new targets for enhancement morphine analgesia and attenuation morphine tolerance.