Heritability of nociception and antinociception in the laboratory mouse

Nociceptive and antinociceptive variability has been demonstrated in the mouse; a proportion of this variability is due to inherited genetic factors. We present genetic correlation analyses of 22 nociceptive measures among a common set of inbred mouse strains, revealing the existence of five fundamental “types” of nociception: (1) baseline thermal; (2) spontaneous responses to noxious chemical stimuli; (3) thermal hyperalgesia; (4) mechanical allodynia; and (5) afferent input-dependent hypersensitivity. To facilitate the identification of polymorphic, nociception-related gene(s), we performed quantitative trait locus (QTL) mapping studies of nociception. We found two significant QTLs, associated with chemical/inflammatory nociception, on chromosomes 9 and 10. Also featuring considerable genetically determined variability is pain inhibition. The pharmacogenetics of morphine analgesia is fairly well characterized, but far less is known about other analgesics. In a systematic study of variable antinociceptive sensitivity to morphine and four non-μ-opioid analgesics in mice, we unexpectedly observed moderate-to-high genetic correlations of strain sensitivities to the five drugs, as well as between baseline nociceptive sensitivity and subsequent antinociceptive response to each drug. Despite the fact that each drug activates unique receptors, our results suggest that common gene(s) affect antinociceptive sensitivity to drugs that modulate descending inhibitory circuitry, and may affect antinociception indirectly, via primary action on baseline nociceptive sensitivity. We similarly assessed the pharmacogenetics of three over-the-counter analgesics, but using a more sensitive nociceptive assay due to the weak efficacy and potency of these drugs. Robust strain differences were also observed, and the two non-steroidal antiinflammatory drugs tested, lysine-aspirin and indomethacin, displayed genetic correlation, whereas acetaminophen variability appeared to be mediated by dissociable genetic factors. We conclude that: (1) both sensitivity to nociception and antinociception are heritable, and QTLs mediating variability in these traits can be identified in mice; (2) common gene(s) underlie sensitivity to nociception within certain ‘types’ of nociceptive assays; and, (3) common gene(s) underlie antinociceptive sensitivity to drugs sharing neural circuitry if not molecular binding sites.