基于外侧缰核βCaMKII过表达诱导的抑郁表型对疼痛的影响及可能机制

Pain is one of the most common psychological issues facing depression patients, often exacerbating their psychosomatic suffering. Currently no effective therapy is available due to lack of understanding about the mechanisms by which depression causes pain. Habenula, a brain structure that has critical roles in connecting forebrain limbic system with monoamine centers in midbrain, has emerged as a major player in depression and pain pathogenesis. βCaMKII’s overexpression in lateral habenula significantly elevates habenula’s neuronal activity and consequently causes depression, but its role in depression-caused pain is still unclear. We hypothesize that hyperactivated LHb neurons regulate the acute and chronic pain by regulating the pain descending circuits. In our study, we will establish a model of pathological pain in depression using mice with βCaMKII overexpression in LHb. On this model we will investigate the role of depression in acute and chronic pain pathogenesis and the underlying mechanisms using pain-related behavioral tests, in vivo pharmacology methods and circuit tracing and manipulation techniques such as DREADD. Our investigation will reveal how the central nervous system is involved in the co-morbidity of pain and depression, which will guide future development of novel therapeutics for pain relief in depression.

不明原因的疼痛是抑郁症中常见的症状，给患者身心带来巨大的伤害。目前，对抑郁伴随的慢性躯体痛的发生和发展机制，还知之甚少。因此，也缺乏有效的治疗手段。缰核作为联系前脑边缘系统和中脑单胺中心的枢纽，在疼痛和抑郁中具有重要作用。研究表明，外侧缰核βCaMKII是缰核过度兴奋引发抑郁的关键分子，但其在抑郁伴随的急慢性疼痛中的作用，仍不清楚。我们假设，外侧缰核神经元的过度兴奋，通过影响与痛觉下行抑制系统相关的脑区及环路的功能，从而对急性和慢性疼痛产生调节。本课题拟在外侧缰核过表达βCaMKII构建小鼠抑郁模型的基础上，建立病理性疼痛动物模型，并运用动物痛行为学测定、在体药理学手段、环路追踪和DREADD介导的环路操控等技术，探讨抑郁对急性痛觉感知和慢性病理性痛觉过敏的作用，及其可能的分子和环路机制。本项目的开展，对于阐明基于外侧缰核过度兴奋的疼痛抑郁共病的中枢机制，寻找新型的治疗靶点，具有重要意义。

疼痛和抑郁共病是长期以来的临床现象，对慢性痛或抑郁症的治疗都带来困难。因二者在治疗药物和治疗反应上的相似性，推测慢性痛和抑郁症可能存在共同的神经生物学机制。缰核作为联系前脑边缘系统和中脑单胺中心的枢纽，在疼痛和抑郁中具有重要作用。本项目的研究一方面通过构建了新型的稳定的外侧缰核βCaMKII过表达的抑郁动物模型，研究了抑郁动物的生理和病理性疼痛的改变，发现βCaMKII过表达的抑郁动物热痛觉敏化。另一方面探索了传统的麻醉镇痛药物氯胺酮的快速抗抑郁机制。发现低于麻醉剂量的氯胺酮通过阻断外侧缰核中，NMDAR和T-VSCC依赖的簇状放电，进而释放对下游单胺类奖赏脑区的过度抑制，最终产生快速抗抑郁效果。本项目从抑郁对疼痛的影响及疼痛对抑郁的作用（麻醉镇痛药物的抗抑郁机制）双向研究了抑郁和疼痛共病的现象和机制。对于阐明基于外侧缰核过度兴奋的疼痛抑郁共病的中枢机制，寻找新型的治疗靶点，具有重要意义。