Neuropathic Pain-induced Depression: the Role of mPFC Endocannabinoids

慢性疼痛是一个重大的公共卫生挑战，但没有得到充分解决。慢性炎症的神经基质 疼痛包括许多中枢神经系统（CNS）过程的破坏，并且抑郁是常见的 慢性疼痛的后果。内侧前额叶皮层（mPFC）是调节抑郁症的关键大脑区域， 锡永症的发生与mPFC中突触功能的破坏有关， 内源性大麻素（endocannabinoid，eCB）系统。此外，解剖和电生理研究 显示传入伤害性通路连接到mPFC。我们假设急性疼痛最初会引起 CB 1 R过度活化，最终导致CB 1 R下调，导致GABA能内 mPFC锥体神经元的支配持续为mPFC活性降低的慢性期，最终 结果是行为抑郁症。这一假设得到了初步数据的支持，这些数据显示， 神经损伤急性期mPFC锥体神经元的活性和升高的2-花生四烯酸甘油 疼痛，慢性脱敏CB 1 R，导致mPFC锥体神经元失活，失活 在动物中引起抑郁样行为的mPFC锥体神经元的支配。拟议的实验 将证实这些有希望的发现，探索机制细节，并探索可能的治疗方法。具体- 最后，Aim 1实验将确定eCB信号传导、mPFC活性和抑郁样神经元的时程。 在神经病理性疼痛的早期和晚期阶段。目的2将检查mPFC突触功能的状态， 疼痛的起始以及在这些条件下eCB水平和突触功能之间的因果关系。菲- 最后，Aim 3将使用不同的方法来调节这一信号通路，以验证其机制。 目的1和2的发现，并为潜在的治疗策略奠定基础。完成亲- 提出的项目不仅将产生新的见解抑郁症的起源在神经性疼痛，而且 可能为基于选择性预防的新型抗抑郁治疗提供概念验证基础 或逆转疼痛诱导的CNS突触可塑性。

Chronic pain is a major public health challenge that is inadequately addressed. The neural substrate of chronic pain includes disruption of numerous central nervous system (CNS) processes, and depression is a common consequence of chronic pain. The medial prefrontal cortex (mPFC) is a key brain area that regulates depres- sion, and the development of depression has been linked to disrupted synaptic function in the mPFC involving signaling through the endocannabinoid (eCB) system. Additionally, anatomical and electrophysiological studies show that afferent nociceptive pathways connect to the mPFC. We hypothesize that acute pain initially induces excess CB1R activation that eventually leads to CB1R downregulation, resulting in elevated GABAergic inner- vation of mPFC pyramidal neurons that persists as a chronic phase of reduced mPFC activity, with the final result being behavioral depression. This hypothesis is supported by preliminary data that reveal increased ac- tivity of mPFC pyramidal neurons and elevated 2-arachidonoylglycerol during the acute phase of nerve injury pain, and chronically desensitized CB1Rs that results in deactivation of mPFC pyramidal neurons, and deacti- vation of mPFC pyramidal neurons that cause depression-like behavior in animals. The proposed experiments will substantiate these promising findings, probe mechanistic details, and explore possible therapies. Specifi- cally, Aim 1 experiments will identify time courses of eCB signaling, mPFC activity, and depression-like behav- ior at early and late phases of neuropathic pain. Aim 2 will examine the state of mPFC synaptic function after initiation of pain and the causal linkage between eCB levels and synaptic function under these conditions. Fi- nally, Aim 3 will use diverse approaches to modulate this signaling pathway in order to verify the mechanistic findings of Aim 1 and 2, and to lay the groundwork for potential therapeutic strategies. Completion of the pro- posed project will not only generate new insights into the genesis of depression in neuropathic pain, but also may provide the proof-of-concept foundation for novel antidepressant treatments based on selective prevention or reversal of pain-induced CNS synaptic plasticity.