前扣带回多巴胺D1/D2受体调控应激致术后疼痛慢性化的作用机制

Patients who have chronic pain induced by post-surgery always recover very slowly.The anterior cingulate cortex (ACC) is the modulatory center of nociceptive sensation. Dopamine receptor D1 and D2 in ACC area are demonstrated to be involved in the modulation of inflammatory pain and acute pain. It is still unclear whether these two receptors participate in the modulation process of postoperative pain chronification. Our study has shown that stress can lead to postoperative pain chronification, and the premiliary data suggests that expression of dopamine receptor D1 and D2 in ACC area increased sharply during pain chorinification process induced by stress. Excitation or inhibition of dopamine receptor D1 by optogetic stimulation in D1-Cre mice may increase pain. Accordingly, we hypothesize that dopamine receptor D1 or D2 in ACC area may exert different functions in modulation of pain chronification induced by stress after surgery. Base on this, we aim to modulate the activities of D1 or D2-expressing neurons by optogenetic stimulation in D1-Cre or D2-Cre mice, and observe the pain behavior changes and molecular techniques, to explore the underlying mechanisms during pain chronification induced by stress after surgery. It would provide new strategies and evidences for clinical pain prevention.

术后慢性疼痛不利于患者术后康复。前扣带回(anterior cingulate cortex,ACC)是伤害性刺激情绪体验中心,ACC区多巴胺受体D1/D2参与炎性痛和急性痛的调制，是否参与术后慢性痛的调控仍不清楚。我们的研究表明应激可导致术后疼痛慢性化，预实验提示在应激导致的术后慢性痛过程中ACC区多巴胺神经元放电异常，D1和D2受体表达明显变化；通过激活ACC区多巴胺D1或D2受体可明显加重或减轻应激导致的术后疼痛。据此我们推测ACC区多巴胺受体可以调控应激导致的术后疼痛慢性化过程。我们将通过建立应激导致的术后疼痛慢性变动物模型、利用光遗传学技术，结合D1-Cre或D2-Cre小鼠，调控ACC区D1/D2受体活性，通过行为学测试、分子生物学等技术，探讨应激导致的术后疼痛慢性化可能的调控机制，以期调控术后疼痛慢性化过程，为临床防治术后慢性疼痛提供思路和依据。

术后慢性疼痛是一个世界性的医学和社会问题，它与多种危险因素有关。我们先前研究表明应激刺激可导致术后疼痛慢性化，脊髓AMPA受体磷酸化介导了这一术后疼痛慢性化机制。慢性应激诱导的持续高水平的糖皮质激素影响小胶质细胞的促炎反应。然而，脊髓小胶质细胞在疼痛发生和维持中的这一关键作用对应激诱导的术后长时间疼痛是否存在性别差异未见报道。多巴胺(DA)是中脑皮质回路中的一种重要的神经调质，调节工作记忆和厌恶情绪。已知腹侧被盖区（VTA）DA输入到皮质调节可塑性，但是否影响疼痛以及如何影响疼痛仍未完全清楚。本研究通过建立应激导致的术后疼痛慢性化动物模型，利用光遗传学技术调控多巴胺通路，探讨应激导致的术后疼痛慢性化可能的调控机制。我们的结果表明，围手术期暴露于社会挫败应激可以诱导小鼠产生长期的术后疼痛，但脊髓小胶质细胞的激活在应激诱导的从急性到长时间的术后疼痛转变中的关键作用存在性别依赖性。通过光遗传学，我们还发现激活VTA区域的多巴胺能神经元可以缓解切口引起的急性疼痛和应激引起的持续性的术后疼痛。综上，我们发现脊髓背角小胶质细胞的激活和VTA区DA信号参与到围手术期社会挫败应激致疼痛慢性化过程中，未来在围手术期通过多种方法抑制脊髓背角小胶质细胞的激活或者调控中脑多巴胺能神经元的活性可能作为治疗应激致术后疼痛慢性化的有效手段。