Peripheral capsaicin reverses nerve injury–associated maladaptive brain networks in male rats: a simultaneous chemogenetic-functional magnetic resonance imaging study

Abstract Chronic pain is associated with maladaptive reorganization of brain networks, particularly in the anterior cingulate cortex (ACC), contributing to the affective dimension of pain. Although peripheral capsaicin administration relieves neuropathic pain in clinics, its effects on central pain networks remain unclear. In this study, we determined the resting-state functional connectivity of ACC (ACC FC) rearrangement after infraorbital nerve chronic constriction injury (ION-CCI) and subsequent peripheral administration of capsaicin through longitudinal resting-state functional magnetic resonance imaging (fMRI) in male rats. We also conducted functional silencing of the ACC using inhibitory chemogenetic receptors to determine ACC networks commonly reversed by peripheral capsaicin and chemogenetic silencing. Infraorbital nerve chronic constriction injury produced orofacial mechanical allodynia accompanied by ACC FC changes compared to sham. A single injection of capsaicin into the maxillary skin decreased mechanical allodynia. Five days after capsaicin injection, CCI-enhanced ACC FC was significantly reduced compared to the time point before the injection in the same rats or to the rats with vehicle injection. Subsequent chemogenetic silencing of ACC in the previously vehicle-treated CCI rats reduced mechanical allodynia and suppressed CCI-enhanced ACC FC. Peripheral capsaicin and chemogenetic inhibition of ACC commonly reversed approximately one-third of the CCI-enhanced ACC FC. Affected regions included the bilateral cingulate areas, primary and secondary somatosensory cortex, primary and secondary auditory areas, hippocampus, and temporal association cortex. We conclude that peripheral capsaicin administration reverses maladaptive ACC networks in male rats with nerve injury and that peripheral nociceptors contribute to the maintenance chronic pain and peripherally targeted treatment can produce long-lasting analgesia.