中央杏仁核内CaMKⅡ在神经病理性痛大鼠调节吗啡耐受的作用和机制

吗啡是临床最常用镇痛药物，但长期使用所产生的耐受却大大限制其临床应用。钙/钙调蛋白依赖性蛋白激酶Ⅱ（CaMKⅡ）不仅是疼痛转为慢性持续性痛关键信号分子，且参与吗啡耐受。我们前期研究发现，在神经病理性痛大鼠CaMKⅡ抑制剂KN93、AIP可产生剂量依赖性镇痛作用；预实验显示在慢性吗啡耐受大鼠中央杏仁核内CaMKⅡ抑制剂AIP可显著增强腹腔注射吗啡镇痛作用，翻转吗啡耐受，提示CaMKⅡ能快速改变吗啡耐受状态，提高吗啡镇痛效果。吗啡耐受关键是mu-受体失敏和内化，故本课题将从CaMKⅡ与mu-受体直接作用及CaMKⅡ调节mu-受体内化、循环、插膜间接作用角度探讨CaMKⅡ调节神经痛-慢性吗啡耐受机制，并将所得结果在大鼠整体实验加以验证。该研究将阐明中央杏仁核内CaMKⅡ调节mu-受体含量机制，为抑制吗啡耐受发生发展，提高吗啡对神经病理性痛治疗效果提供实验依据。

Morphine is one of the most commonly used analgesics in clinic, but long-term use is limited by morphine tolerance. CaMKⅡ is the key signal molecule in the transformation of persistent pain and also plays an important role in morphine tolerance. In our previous work we found that intra injection of CaMKⅡ inhibitor KN93, AIP induced significant antinociceptive effects in rats with mononeuropathy in a dose dependent manner; In the pre-experiment we found the maintenance of morphine tolerance was blocked by intra-central nucleus of amygdala injection of CaMKⅡ inhibitor AIP in rats, the result suggested that CaMKⅡ could quickly change the morphine tolerance condition and enhance the analgesic effect of morphine. The key in morphine tolerance is mu-receptor desensitization and internalization. So this project will further study the mechanism of CaMKⅡin neuropathic rats with chronic morphine tolerance, from the direct action of CaMK II and mu- receptor, CaMK II regulation of mu-receptor transport process angle. The results obtained will be verified by the animal experiment in mononeuropathic rats. This study will elucidate the mechanism of CaMKⅡ to regulate mu-receptor in the central nucleus of amygdala and provide the experimental basis for inhibition of morphine tolerance to improve the treatment on neuropathic pain.