Sex differences in the antagonism of swim stress-induced analgesia: effects of gonadectomy and estrogen replacement

Abstract

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 micrograms/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.(ABSTRACT TRUNCATED AT 250 WORDS)

Gonadal steroid hormone modulation of nociception, morphine antinociception and reproductive indices in male and female rats

“…The specific effects of each steroid agree with some but not all previous studies, suggesting that procedural or subject variables such as steroid manipulation regimen, type/ intensity of pain, and subject genotype may be important modulators of steroid effect. Gonadal steroids also modulate stress-induced analgesia in adult male and female rodents (Romero et al, 1987;Ryan and Maier, 1988;Mogil et al, 1993), and pregnancy (or comparable ovarian steroid elevations) alter females' analgesic state (Gintzler and Liu, 2000). Taken together, these data indicate that reproductive state and analgesic state -either drug-or environmentally induced -are closely tied and commonly controlled by gonadal steroid hormones.…”

The neuroscience and endocrinology of fibromyalgia

“…As determined by sensitivity to specific receptor antagonists, non-opioid SIA in male mice appears to be mediated by the NMDA subtype of excitatory amino acid receptors. In contrast, female mice display equipotent non-opioid SIA that is dependent on estrogen for its expression and is not sensitive to NMDA antagonist (22). The presence of such qualitative sex differences in brain neurochemistry related to analgesia processes indicates possible sex differences in the clinical efficacy of analgesic agents that may activate these mechanisms.…”

“…Animals also exhibit profound sex differences in the magnitude and mechanisms of analgesia produced by pharmacologic (administration of opioid agonists), electrical (brain stimulation-produced analgesia), or environmental (stress exposure) manipulations (22). For example, stress-induced analgesia (SIA) often occurs at higher levels in male rodents than in females (19).…”

Opioid-mediated pain sensitivity in mice bred for high voluntary wheel running

“…For example, the analgesia (as indexed by the hotplate test) induced in male Swiss-Webster mice after 3 min of forced swimming in cold water (15 8C) was not reversible by naloxone. This analgesia was considered to be nonopioid-mediated and was reversible by NMDA antagonists [27]. Other studies with forced swim tests in mice [15,18] and rats [12], though, have found that the analgesia was reversed by naloxone.…”