Gonadal hormone modulation of mu, kappa, and delta opioid antinociception in male and female rats

Abstract

Previous studies suggest that sex differences in morphine antinociception in rodents might be attributed to the activational effects of gonadal hormones. The present study determined whether hormonal modulation of opioid antinociception in adult rats extends to opioids other than the prototypic mu agonist morphine. Male and female rats were sham-gonadectomized (sham-GDX) or gonadectomized (GDX) and replaced with no hormone, estradiol (E2, females), progesterone (P4, females), E2+P4 (females), or testosterone (males). Approximately 28 days later, nociception was evaluated on the 50 degrees C hot plate and warm water tail withdrawal tests before and after subcutaneous administration of hydromorphone, buprenorphine, U50,488, or SNC 80. In sham-GDX (gonadally intact) rats, the mu agonists and U50,488 were less effective in females than in males in at least one nociceptive test, and the delta agonist SNC 80 was less effective in males than in females. In males, gonadectomy tended to decrease, and testosterone tended to increase antinociception produced by 3 of the 4 agonists. In females, gonadectomy and hormone treatment had more variable effects, although E2 tended to decrease mu opioid antinociception. The present results suggest that activational effects of gonadal hormones are relatively modest and somewhat inconsistent on antinociception produced by various opioid agonists in the adult rat.

Perspective: This study demonstrates that reproductive hormones such as testosterone in males and estradiol in females do not consistently modulate sensitivity to the analgesic effects of opioids in the adult organism.

Figure 1.

Effects of estrous stage, gonadectomy, and hormone replacement on basal nociception in the 50°C hot plate test (upper panels) and 50°C warm water tail withdrawal test (lower panels). Each bar is the mean ± 1 standard error of mean (SEM) of 21-28 rats. Treatment group abbreviations: GDX, gonadectomized; 0, no hormone; T, testosterone; E2, estradiol; P4, progesterone; Sham-D, intact females tested during diestrus-1; Sham-P, intact females tested during proestrus; Sham-E, intact females tested during estrus. *Significantly different from GDX + 0 of same sex, P ≤ .05. ^#Significantly different from sham males, P ≤ .05.

Figure 2.

Effects of estrous stage, gonadectomy, and hormone replacement on hydromorphone antinociception in the 50°C hot plate test (upper panels) and 50°C warm water tail withdrawal test (lower panels). Each point is the mean ± 1 SEM of 7-14 rats. Treatment group abbreviations: GDX, gonadectomized; 0, no hormone; T, testosterone; E2, estradiol; P4, progesterone; Sham-D, intact females tested during diestrus-1; Sham-P, intact females tested during proestrus; Sham-E, intact females tested during estrus. *Significantly different from GDX + 0 of same sex, P ≤ .05.

Figure 3.

Effects of estrous stage, gonadectomy, and hormone replacement on buprenorphine antinociception in the 50°C hot plate test (upper panels) and 50°C warm water tail withdrawal test (lower panels). Each point is the mean ± 1 SEM of 8-12 rats. Treatment group abbreviations: GDX, gonadectomized; 0, no hormone; T, testosterone; E2, estradiol; P4, progesterone; Sham-D, intact females tested during diestrus-1; Sham-P, intact females tested during proestrus; Sham-E, intact females tested during estrus. *Significantly different from GDX + 0 of same sex, P ≤ .05.

Figure 4.

Effects of estrous stage, gonadectomy, and hormone replacement on U50,488 antinociception in the 50°C hot plate test (upper panels) and 50°C warm water tail withdrawal test (lower panels). Each point is the mean ± 1 SEM of 5-15 rats. Treatment group abbreviations: GDX, gonadectomized; 0, no hormone; T, testosterone; E2, estradiol; P4, progesterone; Sham-D, intact females tested during diestrus-1; Sham-P, intact females tested during proestrus; Sham-E, intact females tested during estrus. *Significantly different from GDX + 0 of same sex, P ≤ .05.

Figure 5.

Effects of estrous stage, gonadectomy, and hormone replacement on SNC 80 antinociception in the 50°C hot plate test (upper panels) and 50°C warm water tail withdrawal test (lower panels). Each point is the mean ± 1 SEM of 8-10 rats. Treatment group abbreviations: GDX, gonadectomized; 0, no hormone; T, testosterone; E2, estradiol; P4, progesterone; Sham-D, intact females tested during diestrus-1; Sham-P, intact females tested during proestrus; Sham-E, intact females tested during estrus. *Significantly different from GDX + 0 of same sex, P ≤ .05. For visual clarity, some data points at 3.2 mg/kg (all at or near zero) are not shown.