This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Increasing evidence suggests that genetic factors contribute to individual differences in pain perception and analgesic responses. Over the past decade a burgeoning rodent literature has demonstrated genetic influences on nociceptive and anti-nociceptive responses. Limited research regarding genetic influences on pain and analgesia is available in humans; although, two recent studies have reported associations between specific single nucleotide polymorphisms SNP and experimental pain responses. Interestingly, multiple pain-related genetic associations identified in rodents and in humans have been sex-dependent. Therefore, we propose the following translational approach to investigating genetic influences on pain and analgesia, and the sex-dependence thereof. First, recent and emerging findings from quantitative trait locus QTL mapping in mice from Dr. Mogil's lab will identify candidate genes that influence variability in nociceptive and analgesic sensitivity. Second, the association of these candidate genes to pain sensitivity and analgesic responses in humans will be determined using sophisticated, clinically relevant psychophysical procedures. Third, pharmacologic and molecular approaches will be used to elucidate the mechanisms underlying the newly discovered sex-related genetic association to pain and/or opioid analgesia. We plan to characterize associations of the melanocortin-1 receptor gene MC1R to basal pain sensitivity and opioid analgesia and to determine the sex-dependence of these associations; and characterize the association of the beta-opioid receptor gene OPRM, the beta-opioid receptor gene OPRD, and the beta-opioid receptor gene OPRK to basal pain sensitivity and opioid analgesic responses.
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