Many patients with chronic pain conditions suffer from depression. The mechanisms underlying pain-induced depression are still unclear. There are critical links of medial prefrontal cortex (mPFC) synaptic function to depression, with signaling through the endocannabinoid (eCB) system as an important contributor. We hypothesized that afferent noxious inputs after injury compromise activity-dependent eCB signaling in the mPFC, resulting in depression. Depression-like behaviors were tested in male and female rats with traumatic neuropathy [spared nerve injury (SNI)], and neuronal activity in the mPFC was monitored using the immediate early gene c-fos and in vivo electrophysiological recordings. mPFC eCB Concentrations were determined using mass spectrometry, and behavioral and electrophysiological experiments were used to evaluate the role of alterations in eCB signaling in depression after pain. SNI-induced pain induced the development of depression phenotypes in both male and female rats. Pyramidal neurons in mPFC showed increased excitability followed by reduced excitability in the onset and prolonged phases of pain, respectively. Concentrations of the eCBs, 2-arachidonoylglycerol (2-AG) in the mPFC, were elevated initially after SNI, and our results indicate that this resulted in a loss of CB1R function on GABAergic interneurons in the mPFC. These data suggest that excessive release of 2-AG as a result of noxious stimuli triggers use-dependent loss of function of eCB signaling leading to excessive GABA release in the mPFC, with the final result being behavioral depression.

SIGNIFICANCE STATEMENT Pain has both somatosensory and affective components, so the complexity of mechanisms underlying chronic pain is best represented by a biopsychosocial model that includes widespread CNS dysfunction. Many patients with chronic pain conditions develop depression. The mechanism by which pain causes depression is unclear. Although manipulation of the eCB signaling system as an avenue for providing analgesia per se has not shown much promise in previous studies. An important limitation of past research has been inadequate consideration of the dynamic nature of the connection between pain and depression as they develop. Here, we show that activity-dependent synthesis of eCBs during the initial onset of persistent pain is the critical link leading to depression when pain is persistent.

许多患有慢性疼痛的患者患有抑郁症。疼痛诱发抑郁症的机制尚不清楚。内侧前额叶皮层 (mPFC) 突触功能与抑郁症之间存在关键联系，通过内源性大麻素 (eCB) 系统发出信号是一个重要因素。我们假设损伤后传入的有害输入会损害 mPFC 中的活动依赖性 eCB 信号，从而导致抑郁。在患有创伤性神经病变 [神经损伤 (SNI)] 的雄性和雌性大鼠中测试抑郁样行为，并使用即时早期基因cfos和体内监测 mPFC 中的神经元活动电生理记录。使用质谱法测定 mPFC eCB 浓度，并使用行为和电生理实验来评估 eCB 信号传导改变在疼痛后抑郁症中的作用。SNI 诱导的疼痛诱导雄性和雌性大鼠出现抑郁表型。mPFC 中的锥体神经元表现出兴奋性增加，随后分别在疼痛发作和延长阶段的兴奋性降低。eCB 的浓度，即 mPFC 中的 2-花生四烯酸甘油 (2-AG)，在 SNI 后最初升高，我们的结果表明这导致 mPFC 中 GABA 能中间神经元的 CB1R 功能丧失。

重要性声明疼痛同时具有躯体感觉和情感成分，因此慢性疼痛机制的复杂性最好由包括广泛的中枢神经系统功能障碍的生物心理社会模型来表示。许多患有慢性疼痛的患者会患上抑郁症。疼痛导致抑郁的机制尚不清楚。尽管将 eCB 信号系统作为提供镇痛的途径本身在以前的研究中并没有显示出太大的希望。过去研究的一个重要限制是没有充分考虑疼痛和抑郁发展过程中之间联系的动态性质。在这里，我们表明在持续性疼痛的初始发作期间 eCB 的活动依赖性合成是导致疼痛持续时抑郁的关键环节。