SEX-DIFFERENCES IN THE ANTAGONISM OF SWIM STRESS-INDUCED ANALGESIA - EFFECTS OF GONADECTOMY AND ESTROGEN REPLACEMENT

Sex differences in the neurochemical mediation of swim stress-induced analgesia (SSIA) were examined in Swiss-Webster mice. Intact and gonadectomized adult mice of both sexes were tested for their analgesic response (hot-plate test) to 3 min of forced swimming in 15-degrees-C and 20-degrees-C water. SSIA resulting from 15-degrees-C swim was previously shown to be naloxone-insensitive (i.e., non-opioid) whereas SSIA resulting from 20-degrees-C swim produced an analgesia that was partially reversible by naloxone (i.e., mixed opioid/non-opioid). The non-opioid components of these SSIA paradigms were attenuated by the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801). We now report that in males, but not females, dizocilpine (0.075 mg/kg, i.p.) and naloxone (10 mg/kg, i.p.) antagonized the non-opioid and opioid components of SSIA, respectively. After ovariectomy, females displayed a pattern of antagonism similar to males such that dizocilpine attenuated non-opioid SSIA, although naloxone remained ineffective in antagonizing 20-degrees-C SSIA. Thus, SSIA in intact females was neither opioid- nor NMDA-mediated, yet it was of similar magnitude to the SSIA displayed by intact males. In separate experiments, estrogen replacement (estrogen benzoate; 5.0 mug/day, i.p.) administered to ovariectomized mice over a 6-8 day period reinstated the dizocilpine-insensitivity of 15-degrees-C SSIA characteristic of intact females. However, a similar estrogen regimen administered to both intact and castrated males did not compromise the sensitivity to dizocilpine previously noted in male mice. These findings suggest the existence of a novel female-specific estrogen-dependent mechanism of SSIA and highlight the need to consider gender as a factor in basic and clinical research in this area.