Progesterone rapidly recruits female-typical opioid-induced hyperalgesic mechanisms.

Continuous morphine treatment can paradoxically increase nociception (i.e. hyperalgesia) in male and female mice, but sex differences have been reported. Here, we studied progesterone modulation of these differences by assessing nociception on the tail-withdrawal test in male and female mice rendered hyperalgesic during continuous infusion of two different morphine doses (1.6 and 40.0mg/kg/24h). Although the lower morphine infusion dose increased nociception in both sexes by infusion Day 4, this hyperalgesia dissipated by Day 6 in males and ovariectomized females, but not gonadally intact females. A single subcutaneous progesterone (0.0016mg/kg) injection to males and ovariectomized females on Day 6 caused hyperalgesia to recur within 30min and to persist for a minimum of 120min. The larger morphine infusion dose also increased nociception in both sexes on Days 4 and 6. However, the NMDA receptor antagonist MK-801 (0.05mg/kg) reversed hyperalgesia in males and ovariectomized females but not gonadally intact females on infusion Day 6. Subcutaneous progesterone (0.0016mg/kg) injection inhibited this reversal in male and ovariectomized female mice but had no effect on nociception in saline-infused mice of either sex. These data confirm our previous findings that male and female mice utilize distinct hyperalgesic mechanisms, and show for the first time that a single progesterone bolus dose can recruit female-typical hyperalgesia in ovariectomized females and males.

Long-term effects of neonatal surgery on adulthood pain behavior.

The long-term consequences of neonatal noxious stimulation on adulthood pain behavior were investigated in male and female mice. On the day of birth, mouse pups were exposed to a laparotomy under cold anesthesia followed by an analgesic dose of morphine (10 mg/kg) post-operatively, or a saline control. An additional group of subjects was exposed to the non-noxious aspects of the surgical procedure (cold exposure, separation from the dam, injection) comprising a 'sham' surgery control group, whereas another group of control subjects was administered an injection of saline or morphine, but was otherwise undisturbed. Behavioral observations of the pups immediately following the procedure indicated that the laparotomy produced increased distress vocalizations in the ultrasonic range (40 kHz) compared to both groups of control subjects. During 90 min observations periods following the surgery and 1-week later, maternal care did not vary among treatment conditions. In adulthood, offspring were tested for nociceptive sensitivity on the hot-plate (HP; 53 degrees C), tail-withdrawal (TW; 50 degrees C) and acetic acid abdominal constriction test (AC). On both the TW and the AC tests, neonatal surgery decreased pain behavior relative to both groups of control subjects, an effect that was reversed by post-operative morphine treatment. On the HP test, both groups of subjects exposed to the stressful aspects of neonatal surgery (laparotomy or sham surgery) exhibited decreased pain behavior in adulthood. These findings suggest that early exposure to noxious and/or stressful stimuli may induce long-lasting changes in pain behavior, perhaps mediated by alterations in the stress-axis and antinociceptive circuitry.

Acute progesterone can recruit sex-specific neurochemical mechanisms mediating swim stress-induced and kappa-opioid analgesia in mice.

There is a qualitative sex difference in the neurochemical mediation of stress-induced and kappa-opioid analgesia; these phenomena are dependent on N-methyl-d-aspartic acid (NMDA) receptors in males but not females. Progesterone modulation of this sex difference was examined in mice. Analgesia against thermal nociception was produced by forced cold water swim or by systemic administration of the kappa-opioid agonist, U50,488. As seen previously, the NMDA receptor antagonist MK-801 blocked both forms of analgesia in male but not female mice. Also as in previous studies, this sex difference was found to be dependent on ovarian hormones such that ovariectomy induced female mice to "switch" to the male-like, NMDAergic system. We now demonstrate that a single injection of progesterone (50 microg), systemically administered 30 min before analgesia assessment, is sufficient to restore female-specific mediation of analgesia (i.e., insensitivity to MK-801 blockade) in ovariectomized female mice. The rapidity of this neurochemical "switching" action of progesterone suggests mediation via cell surface receptors or the action of neuroactive steroid metabolites of progesterone.

Qualitative sex differences in kappa-opioid analgesia in mice are dependent on age.

The effects of aging on sex differences in analgesia from the kappa-opioid agonist, U50,488H (U50), were examined in C57BL/6J mice. U50 analgesia can be blocked by the N-methyl-d-aspartate receptor antagonist, MK-801 (MK), in male rodents and gonadectomized females, but not hormonally intact or estrogen-replaced females, suggesting the existence of alternate neurochemical mediation in females. We now report that MK antagonism of U50 analgesia is age-dependent in females. That is, reproductively senescent females display MK-sensitive U50 analgesia qualitatively similar to that displayed by males or hormonally deprived young females. Age-related reductions in U50 analgesic magnitude were also observed in females. Thus, age and gender are likely to alter the clinical efficacy of analgesic drugs active at kappa-opioid receptors.

Neonatal testosterone exposure influences neurochemistry of non-opioid swim stress-induced analgesia in adult mice.

The effects of neonatal hormone manipulations on swim stress-induced analgesia (SSIA) magnitude and neurochemical quality were examined in Swiss-Webster mice of both sexes. Previous research has indicated that non-opioid SSIA mechanisms in adult Swiss-Webster mice are sexually dimorphic. Male mice exhibit non-opioid SSIA following a 3-min swim in cold (15 degrees C) water that is antagonized by the non-competitive NMDA antagonist MK-801 (dizocilpine; 0.075 mg/kg), whereas female mice do not display NMDA-mediated analgesia in the presence of estrogen. Since male and female mice show equipotent magnitudes of SSIA, it was concluded that female mice display a neurochemically distinct, estrogen-dependent SSIA mechanism specific to their gender. In the present study, female mice exposed to testosterone during the neonatal period display NMDA-mediated analgesia even in the presence of estrogen in adulthood. Thus, expression of the female-specific, estrogen-dependent SSIA mechanism previously described may be dependent on the absence of testosterone during early ontogeny.

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 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)