Peripheral CRH orchestrates neuropathic pain through transcriptional control by SMAD1 and spinal CRHR2 activation

Neuropathic pain is a debilitating condition that lacks effective
treatments. Corticotropin-releasing hormone (CRH) is associated with the
central neural circuits involved in stress and pain. Here, we identified a
peripheral CRH–mediated signaling axis in dorsal root ganglion (DRG) and
spinal neurons underlying neuropathic pain. Spared nerve injury (SNI) in
male mice increased the abundance of CRH in small- and medium-diameter DRG
neurons, specifically within their central terminals in the spinal dorsal
horn. DRG-specific knockdown of CRH alleviated neuropathic pain. SNI
increased Crh expression by inducing the binding of the transcription
factor SMAD1 to the Crh promoter. Silencing SMAD1 in the DRG reduced
neuropathic pain symptoms, which was accompanied by a decrease in the
amount of CRH in the DRG tissue. Pharmacological antagonism of CRH
receptor 2 (CRHR2), but not of CRHR1, attenuated neuropathic pain and
suppressed the activation of spinal neurons and glia. Spinal CRHR2 is
predominantly localized to excitatory neurons and somatostatin-positive
interneurons in the superficial dorsal horn. These findings reveal a
SMAD1-CRH-CRHR2 axis in DRG-to-spine signaling that promotes neuropathic
pain and suggest that CRHR2 antagonists be explored for its management.

神经病理性疼痛（Neuropathic pain）是一种使人衰弱的疾病，目前尚无有效的治疗手段。促肾上腺皮质激素释放激素（CRH）与参与应激与疼痛调控的中枢神经环路密切相关。本研究鉴定出一条存在于背根神经节（DRG）与脊髓神经元中的、由CRH介导的外周信号轴，该轴参与神经病理性疼痛的发生发展。雄性小鼠的 spared神经损伤（spared nerve injury, SNI）模型可使中小型直径背根神经节神经元中CRH的含量升高，尤其是在其投射至脊髓背角的中枢终末区域。背根神经节特异性敲低CRH可缓解神经病理性疼痛。spared神经损伤可通过诱导转录因子SMAD1结合至Crh启动子区域，从而上调Crh的表达。在背根神经节中沉默SMAD1可减轻神经病理性疼痛症状，同时伴随背根神经节组织中CRH含量的降低。对CRH受体2（CRHR2）进行药理学拮抗（而非拮抗CRHR1）可减轻神经病理性疼痛，并抑制脊髓神经元与神经胶质细胞的活化。脊髓中的CRHR2主要表达于脊髓背角浅层的兴奋性神经元与生长抑素阳性中间神经元中。本研究揭示了一条存在于背根神经节至脊髓信号通路中的SMAD1-CRH-CRHR2轴，该轴可促进神经病理性疼痛的发生，并提示可通过开发CRHR2拮抗剂来治疗该疾病。