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

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.