Estrogen receptor-alpha is required for estrogen-induced mu-opioid receptor internalization

J Neurosci Res. 2003 Mar 15;71(6):802-10. doi: 10.1002/jnr.10526.


Endogenous opioid circuits are pivotal for the regulation of sexual receptivity. Treatment of mice with morphine, a preferential mu-opioid receptor (MOR) agonist, severely attenuates lordosis. Estrogen induces internalization of MOR in cell groups of the limbic-hypothalamic lordosis-regulating circuit. Because rapid MOR internalization is mediated by estrogen release of endogenous opioid peptides, internalization has been used as a neurochemical signature of estrogen action in the central nervous system. Together these results indicate that estrogen induces a MOR mediated inhibition of sexual receptivity. To determine which estrogen receptor, estrogen receptor-alpha (ERalpha) or estrogen receptor-beta (ERbeta), mediates MOR internalization, ERalpha knockout (ERalphaKO), ERbeta knockout (ERbetaKO) and wild-type (WT) mice were used in the present study. WT, ERalphaKO and ERbetaKO mice had similar MOR distributions in the limbic-hypothalamic lordosis-regulating circuit. Estrogen treatment internalized MOR in the medial preoptic nucleus of ovariectomized WT and ERbetaKO, but not ERalphaKO mice. Treatment of ERalphaKO mice with the selective endogenous MOR ligand, endomorphin-1, induced levels of MOR internalization similar to WT mice suggesting that MOR in ERalphaKO mice could be activated and were probably functional. The results of the present experiments indicate that ERalpha is required for estrogen-induced MOR internalization and suggest that ERalpha can mediate rapid actions of estrogen.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Estrogens / pharmacology
  • Female
  • Immunohistochemistry
  • Injections, Intraventricular
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Morphine / pharmacology
  • Neural Pathways / physiology
  • Oligopeptides / administration & dosage
  • Oligopeptides / pharmacology
  • Ovariectomy
  • Receptors, Estrogen / metabolism*
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / drug effects
  • Receptors, Opioid, mu / metabolism*
  • Sexual Behavior, Animal / drug effects
  • Sexual Behavior, Animal / physiology*


  • Analgesics, Opioid
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Estrogens
  • Oligopeptides
  • Receptors, Estrogen
  • Receptors, Opioid, mu
  • endomorphin 1
  • Morphine