Key Laboratory for Neuroscience, Ministry of Education of China & National Health Commission of China, Beijing, China; Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Neuroscience Research Institute, Peking University, Beijing, China.
Department of Endocrinology, Peking University First Hospital, Beijing, China.
J Pain. 2024 Aug;25(8):104495. doi: 10.1016/j.jpain.2024.02.009. Epub 2024 Feb 12.
Exacerbation of pain by chronic stress and comorbidity of pain with stress-related disorders such as depression and post-traumatic stress disorder, represent significant clinical challenges. Previously we have documented that chronic forced swim (FS) stress exacerbates neuropathic pain in spared nerve injury (SNI) rats, associated with an up-regulation of GluN2B-containing N-methyl-D-aspartate receptors (GluN2B-NMDARs) in the central nucleus of the amygdala (CeA). However, the molecular mechanisms underlying chronic FS stress (CFSS)-mediated exacerbation of pain sensitivity in SNI rats still remain unclear. In this study, we demonstrated that exposure of CFSS to rats activated the corticotropin-releasing factor (CRF)/CRF receptor type 1 (CRFR1) signaling in the CeA, which was shown to be necessary for CFSS-induced depressive-like symptoms in stressed rats, and as well, for CFSS-induced exacerbation of pain hypersensitivity in SNI rats exposed to chronic FS stress. Furthermore, we discovered that activation of CRF/CRFR1 signaling in the CeA upregulated the phosphorylation of GluN2B-NMDARs at tyrosine 1472 (pGluN2B) in the synaptosomal fraction of CeA, which is highly correlated to the enhancement of synaptic GluN2B-NMDARs expression that has been observed in the CeA in CFSS-treated SNI rats. In addition, we revealed that activation of CRF/CRFR1 signaling in the CeA facilitated the CFSS-induced reinforcement of long-term potentiation as well as the enhancement of NMDAR-mediated excitatory postsynaptic currents in the basolateral amygdala (BLA)-CeA pathway in SNI rats. These findings suggest that activation of CRF/CRFR1 signaling in the CeA contributes to chronic stress-induced exacerbation of neuropathic pain by enhancing GluN2B-NMDAR-mediated synaptic plasticity in rats subjected to nerve injury. PERSPECTIVE: Our present study provides a novel mechanism for elucidating stress-induced hyperalgesia and highlights that the CRF/CRFR1 signaling and the GluN2B-NMDAR-mediated synaptic plasticity in the CeA may be important as potential therapeutic targets for chronic stress-induced pain exacerbation in human neuropathic pain. DATA AVAILABILITY: The data that support the findings of this study are available from the corresponding author upon reasonable request.
慢性应激加剧疼痛，并使疼痛与抑郁和创伤后应激障碍等应激相关障碍共存，这是重大的临床挑战。此前我们已经证明，慢性强迫游泳（FS）应激会加剧 spared nerve injury（SNI）大鼠的神经病理性疼痛，同时导致杏仁中央核（CeA）中含 GluN2B 的 N-甲基-D-天冬氨酸受体（GluN2B-NMDAR）上调。然而，慢性 FS 应激（CFSS）介导的 SNI 大鼠痛觉敏感性加剧的分子机制仍不清楚。在这项研究中，我们证明了 CFSS 暴露于大鼠会激活 CeA 中的促肾上腺皮质释放因子（CRF）/CRF 受体 1（CRFR1）信号，这对于应激大鼠的 CFSS 诱导的抑郁样症状以及 CFSS 诱导的 SNI 大鼠的痛觉过敏加剧是必要的。此外，我们发现 CeA 中的 CRF/CRFR1 信号的激活会使 CeA 突触小体部分的 GluN2B-NMDAR 酪氨酸 1472 磷酸化（pGluN2B）上调，这与 CFSS 处理的 SNI 大鼠 CeA 中观察到的突触 GluN2B-NMDAR 表达增强高度相关。此外，我们揭示了 CeA 中的 CRF/CRFR1 信号的激活促进了 CFSS 诱导的长时程增强以及 SNI 大鼠基底外侧杏仁核（BLA）-CeA 通路中 NMDAR 介导的兴奋性突触后电流的增强。这些发现表明，CeA 中 CRF/CRFR1 信号的激活通过增强神经损伤大鼠中 GluN2B-NMDAR 介导的突触可塑性，导致慢性应激引起的神经病理性疼痛加剧。观点：我们的这项研究提供了一种新的机制来阐明应激引起的痛觉过敏，并强调了 CeA 中的 CRF/CRFR1 信号和 GluN2B-NMDAR 介导的突触可塑性可能是人类神经病理性疼痛慢性应激性疼痛加剧的潜在治疗靶点。数据可用性：支持本研究结果的数据可应合理要求向通讯作者索取。
