Supraspinal contributions to hyperalgesia

Tissue injury is associated with sensitization of nociceptors and subsequen t changes in the excitability of central (spinal) neurons, termed central s ensitization. Nociceptor sensitization and central sensitization are consid ered to underlie, respectively, development of primary hyperalgesia and sec ondary hyperalgesia. Because central sensitization is considered to reflect plasticity at spinal synapses, the spinal cord has been the principal focu s of studies of mechanisms of hyperalgesia. Not surprisingly, glutamate, ac ting at a spinal N-methyl-D-aspartate (NMDA) receptor, has been implicated in development of secondary hyperalgesia associated with somatic, neural, a nd visceral structures. Downstream of NMDA receptor activation, spinal nitr ic oxide (NO), protein kinase C, and other mediators have been implicated i n maintaining such hyperalgesia. Accumulating evidence, however, reveals a significant contribution of supraspinal influences to development and maint enance of hyperalgesia. Spinal cord transection prevents development of sec ondary, but not primary, mechanical and/or thermal hyperalgesia after topic al mustard oil application, carrageenan inflammation, or nerve-root ligatio n. Similarly, inactivation of the rostral ventromedial medulla (RVM) attenu ates hyperalgesia and central sensitization in several models of persistent pain. Inhibition of medullary NMDA receptors or NO. generation attenuates somatic and visceral hyperalgesia, In support, topical mustard oil applicat ion or colonic inflammation increases expression of NO synthase in the RVM. These data suggest a prominent role for the RVM in mediating the sensitiza tion of spinal neurons and development of secondary hyperalgesia. Results t o date suggest that peripheral injury and persistent input engage spinobulb ospinal mechanisms that may be the prepotent contributors to central sensit ization and development of secondary hyperalgesia.