慢性疼痛严重影响了患者的生活质量，然而急性痛慢性化的机制并不十分清楚，急性痛自然转归过程的失败可能是导致疼痛慢性化的原因。申请者发现，β-arrestin2(Arrb2)缺陷可以通过增强NMDAR活性显著延长DAMGO在脊髓早期的镇痛作用及远期的致痛敏作用时程。预实验发现Arrb2-/-小鼠的急性痛敏较正常组显著增强，抑制Arrb2-/-动物背角神经元ERK可降低增强的NMDA电流，同时发现疼痛慢性化过程Arrb2表达下调，提示Arrb2在疼痛慢性化中的作用，但具体机制不清楚。申请者拟应用电生理学、形态学、光遗传学、钙成像、分子生物学等方法，研究β-arrestin2通过调控μ受体失活-复敏环路调控疼痛慢性化过程，深入探讨病理状态下μ受体偏向性改变，通过介导AC-cAMP-ERK活化，激活NMDAR调控疼痛慢性化的具体过程，进一步揭示疼痛慢性化作用机制，为慢性痛的预防和治疗提供依据。

Chronic pain is a serious threat to patients' quality of life and mental and physical health. However, the mechanism of how acute pain transform to chronic pain is still not clear. Intrathecal injection of the mu-opioid receptor agonist DAMGO produces paradoxical behavioural responses: early-phase analgesia and late-phase mechanical allodynia which requires NMDAR; both phases are prolonged in Arrb2 knockout (KO) mice. The preliminary experiment also showed that the acute pain sensitivity of Arrb2-/- mice was significantly increased vs the normal group, and the enhanced NMDAR-induced current in Arrb2-/- mice was reduced when was blocked by ERK inhibitor U0126 in superficial neurons. Applicants intend to use electrophysiology, immunohistochemistry, optogenetics, calcium imaging, molecular biology and other methods to study β-arrestin2 regulates chronic pain by regulating the role of μ receptor desensitization- resensitization cycle, to further explore the pathological changes of μ receptor bias effect, mediated activation of AC-cAMP-ERK, and then active NMDAR and promote acute pain turns into chronic pain, which may reveal the related mechanism of chronic pain, and provide the theoretical basis for the prevention and treatment of chronic pain.