Down-regulation of gastrin-releasing peptide in medial orbitofrontal cortex to nucleus accumbens projections contributes to allodynia and negative affect.

Chronic pain is debilitating with affective comorbidities, but neural mechanisms linking nociception and emotional processing are unclear. Here, we identify the gastrin-releasing peptide (GRP)/GRP receptor (GRPR) system in the medial orbitofrontal cortex (MO)-nucleus accumbens (NAc) pathway as critical for regulating chronic pain and its affective dimensions. Using multimodal approaches (fiber photometry, chemogenetics, optogenetics, and Raman spectroscopy), we show that chronic pain reduces NAc(Grpr) neuron excitability and MO-to-NAc GRP release. Chemogenetic inhibition or GRPR knockdown in NAc(Grpr) neurons induces pain phenotypes in naive mice; optogenetic activation of NAc(Grpr) neurons or NAc GRP supplementation alleviates these in chronic pain mice. MO(Grp)-to-NAc activation mirrors therapeutic effects. Raman mapping shows fivefold lower NAc GRP after nerve injury, correlating with reduced neuronal activity. These findings establish the MO(Grp)-NAc(Grpr) circuit as a central integrator and GRP/GRPR as a dual therapeutic target for chronic pain, uncovering a neuropeptide-mediated cortical-limbic pain mechanism.