Freezing of Enkephalinergic Functions by Multiple Noxious Foci: A Source of Pain Sensitization?

BACKGROUND:The functional significance of proenkephalin systems in processing pain remains an open question and indeed is puzzling. For example, a noxious mechanical stimulus does not alter the release of Met-enkephalin-like material (MELM) from segments of the spinal cord related to the stimulated area of the body, but does increase its release from other segments. METHODOLOGY/PRINCIPAL FINDINGS:Here we show that, in the rat, a noxious mechanical stimulus applied to either the right or the left hind paw elicits a marked increase of MELM release during perifusion of either the whole spinal cord or the cervico-trigeminal area. However, these stimulatory effects were not additive and indeed, disappeared completely when the right and left paws were stimulated simultaneously. CONCLUSION/SIGNIFICANCE:We have concluded that in addition to the concept of a diffuse control of the transmission of nociceptive signals through the dorsal horn, there is a diffuse control of the modulation of this transmission. The "freezing" of Met-enkephalinergic functions represents a potential source of central sensitization in the spinal cord, notably in clinical situations involving multiple painful foci, e.g. cancer with metastases, poly-traumatism or rheumatoid arthritis

Involvement of the Melanocortin-1 Receptor in Acute Pain and Pain of Inflammatory but Not Neuropathic Origin

Response to painful stimuli is susceptible to genetic variation. Numerous loci have been identified which contribute to this variation, one of which, MC1R, is better known as a gene involved in mammalian hair colour. MC1R is a G protein-coupled receptor expressed in melanocytes and elsewhere and mice lacking MC1R have yellow hair, whilst humans with variant MC1R protein have red hair. Previous work has found differences in acute pain perception, and response to analgesia in mice and humans with mutations or variants in MC1R.We have tested responses to noxious and non-noxious stimuli in mutant mice which lack MC1R, or which overexpress an endogenous antagonist of the receptor, as well as controls. We have also examined the response of these mice to inflammatory pain, assessing the hyperalgesia and allodynia associated with persistent inflammation, and their response to neuropathic pain. Finally we tested by a paired preference paradigm their aversion to oral administration of capsaicin, which activates the noxious heat receptor TRPV1. Female mice lacking MC1R showed increased tolerance to noxious heat and no alteration in their response to non-noxious mechanical stimuli. MC1R mutant females, and females overexpressing the endogenous MC1R antagonist, agouti signalling protein, had a reduced formalin-induced inflammatory pain response, and a delayed development of inflammation-induced hyperalgesia and allodynia. In addition they had a decreased aversion to capsaicin at moderate concentrations. Male mutant mice showed no difference from their respective controls. Mice of either sex did not show any effect of mutant genotype on neuropathic pain.We demonstrate a sex-specific role for MC1R in acute noxious thermal responses and pain of inflammatory origin