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| SEX-SPECIFIC GENETIC MEDIATION OF PAIN Jeffrey Mogil, Ph.D., Program in Neuroscience, Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, Illinois In addition to the common if controversial observation of quantitative sex differences in nociceptive and analgesic sensitivity in rodents, we and others have demonstrated the existence of qualitative sex differences in the neurochemical mediation of these phenomena. For instance, whereas male rodents possess a non-opioid endogenous analgesic mechanism involving the activation of N-methyl-D-aspartate (NMDA) receptors, female rodents display equipotent analgesia that is, however, non-opioid and non-NMDAergic (Mogil et al., Pain, 1993). This female-specific analgesia system was originally demonstrated using forced cold water swim as an eliciting stimulus in Swiss-Webster mice, but is now known to generalize to different species, strains, and stressors. In fact, analgesia from kappa-opioid agonists shows an analogous sex difference, being sensitive to NMDA antagonist reversal in males but not females (Kavaliers and Choleris, Brain Res., 1997). Although something is known about the properties of the female-specific system (e.g., Sternberg et al., Pain, 1996), its neurochemical identity remains obscure. Recently, we subjected cold water swim analgesia to quantitative trait locus (QTL) mapping, a technique we have used successfully to localize genes relevant to nociceptive and opioid analgesic sensitivity (Belknap et al., Life Sci, 1995; Mogil et al., Pain, 1997). A sex-specific QTL was identified on the distal portion of mouse chromosome 8; the gene(s) in this region account for up to 25% of the overall trait variance observed in female mice, but are irrelevant to the trait in male mice (Mogil et al., J. Neurosci., 1997). Female mice possessing one or two alleles of this gene derived from the DBA/2 mouse strain exhibit 3-fold increased analgesia compared to female mice possessing the homozygous C57BL/6 genotype. At the present time the identity of the QTL is unknown; positional cloning efforts are underway. However, the very existence of a major female-specific QTL can be taken as strong independent confirmation of a female-specific analgesic mechanism. A male-specific QTL mediating thermal nociceptive sensitivity and/or opioid analgesia has also been identified on distal mouse chromosome 4 (Mogil et al., Pain, 1997). A plausible candidate gene for this QTL is Oprd1, encoding the mouse delta-opioid receptor. Finally, in recent studies, we have provided evidence that sex differences in supraspinal morphine analgesia also may have a genetic basis. A survey of morphine dose-response relationships in eleven inbred mouse strains revealed significant male>female sex differences in three (Kest & Mogil, submitted). We believe that much of the inconsistency in the demonstration of sex differences in opioid analgesia may thus be attributed to the varying genetic backgrounds tested. Intriguingly, we also identified one strain in which female mice were significantly more sensitive to the analgesic effects of morphine than were males. A QTL mapping study involving this strain and both sexes is underway. We conclude from these investigations that quantitative sex differences in nociceptive and analgesic sensitivity may not be due to the modulation of common mechanisms by hormones, but rather to the differential output of separate mechanisms.
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