The contribution of medullary and spinal 5-HT1A receptors to endogenous regulation of neuropathic hypersensitivity was studied. Administration of WAY-100635, a 5-HT1A receptor antagonist, into the rostroventromedial medulla or subcutaneously attenuated mechanical hypersensitivity in rats with a spinal nerve injury. Thermal nociception outside of the injured segment was not influenced by medullary or systemic administration of WAY-100635. When administered intrathecally alone, WAY-100635 had no significant effect on pain-related behavior. Suppression of mechanical hypersensitivity induced by medullary administration of WAY-100635 was reversed by intrathecal administration of WAY-100635 or atipamezole, an a2-adrenoceptor antagonist, but not by naloxone, an opioid receptor antagonist. The results indicate that endogenous release of 5-HT, via action on medullary 5-HT1A receptors, tonically suppresses descending inhibition in neuropathic animals. Following medullary administration of a 5-HT1A receptor antagonist, descending pain regulatory pathways are disinhibited and this leads to selective attenuation of neuropathic hypersensitivity, due to action on spinal 5-HT1A and a2-adrenoceptors.