Lesion of the Rostral Anterior Cingulate Cortex Eliminates the Aversiveness of Spontaneous Neuropathic Pain Following Partial or Complete Axotomy

Neuropathic pain is often "spontaneous" or "stimulus-independent." Such pain may result from spontaneous discharge in primary afferent nociceptors in injured peripheral nerves. However, whether axotomized primary afferent nociceptors give rise to pain is unclear. The rostral anterior cingulate cortex (rACC) mediates the negative affective component of inflammatory pain. Whether the rACC integrates the aversive component of chronic spontaneous pain arising from nerve injury is not known. Here, we used the principle of negative reinforcement to show that axotomy produces an aversive state reflecting spontaneous pain driven from injured nerves. Additionally, we investigated whether the rACC contributes to the aversiveness of nerve injury-induced spontaneous pain. Partial or complete hind paw denervation was produced by sciatic or sciatic/saphenous axotomy, respectively. Conditioned place preference resulting from presumed pain relief was observed following spinal clonidine in animals with sciatic axotomy but not in sham-operated controls. Similarly, lidocaine administration into the rostral ventromedial medulla (RVM) produced place preference selectively in animals with sciatic/saphenous axotomy. In rats with spinal nerve ligation (SNL) injury, lesion of the rACC blocked the reward elicited by RVM lidocaine but did not alter acute stimulus-evoked hypersensitivity. Lesion of the rACC did not block cocaine-induced reward, indicating that rACC blockade did not impair memory encoding or retrieval but did impair spontaneous aversiveness. These data indicate that spontaneous pain arising from injured nerve fibers produces a tonic aversive state that is mediated by the rACC. Identification of the circuits mediating aversiveness of chronic pain should facilitate the development of improved therapies.