Chronic stress enhances neuropathic pain through activation of the anterior cingulate cortex-spinal dorsal horn pathway in rats

Chronic stress is known to exacerbate neuropathic pain, yet the underlying mechanisms remain poorly understood. This study investigates the role of the anterior cingulate cortex (ACC) and its descending projections to the spinal dorsal horn (SDH) in mediating stress-induced pain facilitation. Using a chronic unpredictable mild stress (CUMS) model combined with a chronic constriction injury (CCI) model in male Sprague-Dawley rats, we assessed behavioral changes, neuronal activity, and molecular alterations. Our results demonstrate that CUMS significantly exacerbates mechanical allodynia in CCI rats, correlating with increased c-Fos expression in both the ACC and spinal cord, indicative of heightened neuronal activity. Chemogenetic inhibition of ACC-SDH projection neurons alleviated mechanical allodynia without affecting depressive-like behaviors, suggesting a specific role for this pathway in pain modulation. Furthermore, we identified that brain-derived neurotrophic factor (BDNF) signaling in the ACC-SDH pathway is crucial for the facilitation of neuropathic pain under chronic stress conditions. BDNF levels were elevated in the ACC of CUMS+CCI rats, and knockdown of BDNF in ACC-SDH projecting neurons attenuated stress-induced pain sensitivity. Our findings elucidate the functional capabilities of the ACC-SDH pathway in the context of chronic stress and neuropathic pain, highlighting BDNF as a potential therapeutic target for managing pain associated with affective disorders.