Abstract
BackgroundResponse 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.Methodology and Principal FindingsWe 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.ConclusionsWe demonstrate a sex-specific role for MC1R in acute noxious thermal responses and pain of inflammatory origin.
Highlights
The sensation of pain serves as a protective function, by alerting us to real or impending injury, triggering protective responses [1]
We demonstrate a sex-specific role for Melanocortin-1 receptor (MC1R) in acute noxious thermal responses and pain of inflammatory origin
In several strains of mice (AKR/J, C57BL/6J, SWR/J) males appear more sensitive to morphine, whilst in other strains there are no sex differences and in one strain studied (CBA/J) females are more sensitive than males [8]
Summary
The sensation of pain serves as a protective function, by alerting us to real or impending injury, triggering protective responses [1]. There are several rare, hereditary, sensory and autonomic neuropathies (HSANs) which are characterized by failure in development of or by degeneration of primary sensory and autonomic neurons [2] Such conditions can lead to an impaired ability to perceive noxious stimuli and may result in permanent damage as normally painful injuries go unnoticed. It is well established that the sexes differ in their sensitivity to pain and in their responses to analgesia [3,4], with females in general displaying greater sensitivity to pain than males [5,6] This can be dependent upon genetic factors; for example in the Sprague Dawley rat strain, males are more sensitive than females to thermal nociception, while the opposite is seen in the Long Evans rat strain [7]. Previous work has found differences in acute pain perception, and response to analgesia in mice and humans with mutations or variants in MC1R
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