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，但没有得到充分的解决。慢性阻塞性肺疾病的神经基础 疼痛包括许多中枢神经系统(CNS)过程的中断，抑郁是一种常见的 慢性疼痛的后果。内侧前额叶皮质(MPFC)是大脑中调节降压素的关键区域。 Sion，抑郁症的发生与mPFC的突触功能紊乱有关。 通过内源性大麻素(ECB)系统发出信号。此外，解剖学和电生理学研究 显示传入伤害性通路与mPFC相连。我们假设急性疼痛最初会导致 CB1R过度激活，最终导致CB1R下调，导致GABA能内- 作为mPFC活性降低的慢性期持续存在的mPFC锥体神经元的激活，最终 结果表现为行为抑郁。这一假说得到了初步数据的支持，这些数据显示Ac增加。 神经损伤急性期mPFC锥体神经元活性及2-花生四烯酸甘油升高 疼痛，慢性脱敏的CB1Rs，导致mPFC锥体神经元失活，以及失活。 在动物中引起抑郁行为的mPFC锥体神经元的激活。拟议中的实验 将证实这些有希望的发现，探索机械细节，并探索可能的治疗方法。具体来说- Cally，Aim 1实验将确定ECB信号、mPFC活性和抑郁样行为的时间进程- 神经病理性疼痛早期和晚期的IOR。目标2将检查mPFC突触功能的状态 在这些条件下，疼痛的开始以及ECB水平和突触功能之间的因果联系。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 目标1和目标2的发现，并为潜在的治疗策略奠定基础。完成PRO- Proposed项目不仅将对神经病理性疼痛中抑郁的起源产生新的见解，而且 可能为基于选择性预防的新型抗抑郁药物治疗提供概念验证基础 或逆转疼痛诱导的中枢神经系统突触可塑性。

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.