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

J Pain. 2005 Apr;6(4):261-74. doi: 10.1016/j.jpain.2004.12.006.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics, Opioid / metabolism
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Estrogens / metabolism
  • Estrogens / pharmacology
  • Estrous Cycle / physiology
  • Female
  • Gonadal Steroid Hormones / metabolism*
  • Gonadal Steroid Hormones / pharmacology
  • Male
  • Orchiectomy
  • Ovariectomy
  • Pain / drug therapy*
  • Pain / metabolism*
  • Pain / physiopathology
  • Pain Measurement / drug effects
  • Progesterone / metabolism
  • Progesterone / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid / drug effects*
  • Receptors, Opioid / metabolism*
  • Receptors, Opioid, delta / drug effects
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, kappa / drug effects
  • Receptors, Opioid, kappa / metabolism
  • Receptors, Opioid, mu / drug effects
  • Receptors, Opioid, mu / metabolism
  • Sex Characteristics*
  • Testosterone / metabolism
  • Testosterone / pharmacology


  • Analgesics, Opioid
  • Estrogens
  • Gonadal Steroid Hormones
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Testosterone
  • Progesterone