Supraspinal contributions to hyperalgesia

Abstract

Tissue injury is associated with sensitization of nociceptors and subsequent changes in the excitability of central (spinal) neurons, termed central sensitization. Nociceptor sensitization and central sensitization are considered to underlie, respectively, development of primary hyperalgesia and secondary hyperalgesia. Because central sensitization is considered to reflect plasticity at spinal synapses, the spinal cord has been the principal focus of studies of mechanisms of hyperalgesia. Not surprisingly, glutamate, acting at a spinal N-methyl-D-aspartate (NMDA) receptor, has been implicated in development of secondary hyperalgesia associated with somatic, neural, and visceral structures. Downstream of NMDA receptor activation, spinal nitric oxide (NO.), protein kinase C, and other mediators have been implicated in maintaining such hyperalgesia. Accumulating evidence, however, reveals a significant contribution of supraspinal influences to development and maintenance of hyperalgesia. Spinal cord transection prevents development of secondary, but not primary, mechanical and/or thermal hyperalgesia after topical mustard oil application, carrageenan inflammation, or nerve-root ligation. Similarly, inactivation of the rostral ventromedial medulla (RVM) attenuates 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 application or colonic inflammation increases expression of NO. synthase in the RVM. These data suggest a prominent role for the RVM in mediating the sensitization of spinal neurons and development of secondary hyperalgesia. Results to date suggest that peripheral injury and persistent input engage spinobulbospinal mechanisms that may be the prepotent contributors to central sensitization and development of secondary hyperalgesia.

Figure 1

Involvement of descending facilitatory influences from the RVM in models of secondary, but not primary, thermal hyperalgesia after peripheral inflammation. (A) RVM lesion produced by ibotenic acid prevented facilitation of the thermal paw-withdrawal response after intraarticular carrageenan/kaolin injection into the knee (t test, P < 0.05), but was ineffective in preventing facilitation of the thermal paw-withdrawal response after intraplantar carrageenan injection into the foot (model of primary hyperalgesia). (B) Intra-RVM microinjection of the NMDA receptor antagonist APV (1 pmol/1 μl), or (C) intra-RVM microinjection of the neurotensin receptor antagonist SR48692 (3 nmol/1 μl) attenuated secondary, but not primary, hyperalgesia (t test, P < 0.05). All data are represented as mean ± SEM of the percent change in thermal paw-withdrawal latency (%) from the control response for the ipsilateral (inflamed) hindlimb. In experiments involving ibotenic acid RVM lesion, responses are represented at the time of maximal hyperalgesia (3 hr after carrageenan injection). Intra-RVM microinjection of APV or SR48692 was performed at the time of maximal hyperalgesia (3 hr), and responses are represented at the time of maximal drug effect after intra-RVM injection (10 min).

Figure 2

Summary diagram illustrating a significant supraspinal contribution to secondary, but not primary, thermal hyperalgesia after peripheral inflammation. Peripheral injury results in activation and sensitization of peripheral nociceptors and subsequent enhanced excitability of dorsal horn nociceptive neurons (central sensitization) that contributes to primary hyperalgesia (at site of injury) and secondary hyperalgesia (adjacent/distant from site of injury). Additionally, it is proposed that stimulation of nociceptors activates a spinobulbospinal loop, engaging a centrifugal descending nociceptive facilitatory influence from the RVM. Facilitatory influences are activated by NMDA receptors and NO^⋅, and neurotensin (NT) receptors in the RVM and descend to multiple spinal segments to contribute significantly to secondary hyperalgesia. In contrast, primary hyperalgesia does not involve descending facilitatory influences from supraspinal sites and is likely the direct result of peripheral nociceptor sensitization and neuroplasticity intrinsic to the spinal cord. For clarity, the afferent input to the spinal dorsal horn from the site of injury is illustrated as not entering the spinal cord (which it certainly does).