Zhao Weinan, Yu Yu-Mei, Wang Xiao-Yi, Xia Sun-Hui, Ma Yu, Tang Huimei, Tao Mingshu, Li He, Xu Zheng, Yang Jun-Xia, Wu Peng, Zhang Hongxing, Ding Hai-Lei, Cao Jun-Li
Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
Mol Psychiatry. 2024 Jul;29(7):2170-2184. doi: 10.1038/s41380-024-02488-7. Epub 2024 Mar 7.
Both peripheral and central corticotropin-releasing factor (CRF) systems have been implicated in regulating pain sensation. However, compared with the peripheral, the mechanisms underlying central CRF system in pain modulation have not yet been elucidated, especially at the neural circuit level. The corticoaccumbal circuit, a structure rich in CRF receptors and CRF-positive neurons, plays an important role in behavioral responses to stressors including nociceptive stimuli. The present study was designed to investigate whether and how CRF signaling in this circuit regulated pain sensation under physiological and pathological pain conditions. Our studies employed the viral tracing and circuit-, and cell-specific electrophysiological methods to label the CRF-containing circuit from the medial prefrontal cortex to the nucleus accumbens shell (mPFC-NAcS) and record its neuronal propriety. Combining optogenetic and chemogenetic manipulation, neuropharmacological methods, and behavioral tests, we were able to precisely manipulate this circuit and depict its role in regulation of pain sensation. The current study found that the CRF signaling in the NAc shell (NAcS), but not NAc core, was necessary and sufficient for the regulation of pain sensation under physiological and pathological pain conditions. This process was involved in the CRF-mediated enhancement of excitatory synaptic transmission in the NAcS. Furthermore, we demonstrated that the mPFC neurons monosynaptically connected with the NAcS neurons. Chronic pain increased the protein level of CRF in NAcS, and then maintained the persistent NAcS neuronal hyperactivity through enhancement of this monosynaptic excitatory connection, and thus sustained chronic pain behavior. These findings reveal a novel cell- and circuit-based mechanistic link between chronic pain and the mPFC → NAcS circuit and provide a potential new therapeutic target for chronic pain.
外周和中枢促肾上腺皮质激素释放因子（CRF）系统均与疼痛感觉的调节有关。然而，与外周相比，中枢CRF系统在疼痛调制中的潜在机制尚未阐明，尤其是在神经回路水平。皮质-伏隔核回路富含CRF受体和CRF阳性神经元，在对应激源（包括伤害性刺激）的行为反应中起重要作用。本研究旨在探讨该回路中的CRF信号在生理和病理疼痛条件下是否以及如何调节疼痛感觉。我们的研究采用病毒示踪、回路特异性和细胞特异性电生理方法，标记从内侧前额叶皮质到伏隔核壳（mPFC-NAcS）的含CRF回路，并记录其神经元特性。结合光遗传学和化学遗传学操作、神经药理学方法及行为测试，我们能够精确操纵该回路并描述其在疼痛感觉调节中的作用。当前研究发现，在生理和病理疼痛条件下，伏隔核壳（NAcS）而非伏隔核核心中的CRF信号对于疼痛感觉的调节是必要且充分的。这一过程涉及CRF介导的NAcS兴奋性突触传递增强。此外，我们证明mPFC神经元与NAcS神经元单突触相连。慢性疼痛增加了NAcS中CRF的蛋白水平，然后通过增强这种单突触兴奋性连接维持NAcS神经元的持续高活性，从而维持慢性疼痛行为。这些发现揭示了慢性疼痛与mPFC→NAcS回路之间基于细胞和回路的新型机制联系，并为慢性疼痛提供了潜在的新治疗靶点。
