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 predomi..., , Animal models: spared nerve injury (SNI) in rodents. Behavioral tests: Mechanical allodynia: von Frey filaments (paw withdrawal threshold, grams). Motor coordination: Rotarod test (latency, seconds). Molecular assays: qPCR (fold change relative to naïve/sham/treatment group). Immunohistochemistry: CRH, SMAD1, c-Fos, GFAP, IBA1; colocalization with IB4, CGRP, NF200. Pharmacology: CRHR1 antagonist NBI 27914 (1 μg/10 μL, i.t.). CRHR2 antagonist Astressin 2B (0.01–1 μg/10 μL, i.t.). Gene manipulation: siRNA (DRG injection), AAV-shRNA (spinal cord), luciferase promoter assay. , # Peripheral CRH orchestrates neuropathic pain through transcriptional control by SMAD1 and spinal CRHR2 activation Dataset DOI: [10.5061/dryad.sf7m0cgms](https://doi.org/10.5061/dryad.sf7m0cgms) **Descriptions** We have submitted our main quantitative data (aeb3953_data_file.csv), raw microarray data folder (E‑MTAB‑3326/), raw gene expression data folder (GSE75072_RAW/), and dataset description file (README.txt). Key Information Sources Raw microarray data: ArrayExpress (E-MTAB-3326) Raw gene expression data: NCBI GEO (GSE75072) **Usage notes** Microsoft Excel or similar spreadsheet software can be used to view aeb3953_data_file.csv. Microarray data files can be processed using standard bioinformatics tools in R or Python. **Reproducibility Statement** All data required to reproduce the analyses, statistics, and conclusions of the study are fully included. Raw fluorescence microscopy images are not required for quantitative or statistical reproducibility and are not included ...,