SMAD1-mediated induction of peripheral CRH after nerve injury promotes neuropathic pain by activating spinal CRHR2.

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 in 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 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.