Estrogen-induced mu-opioid receptor internalization in the medial preoptic nucleus is mediated via neuropeptide Y-Y1 receptor activation in the arcuate nucleus of female rats.
The endogenous peptides beta-endorphin (beta-END) and neuropeptide Y (NPY) have been implicated in regulating sexual receptivity. Both beta-END and NPY systems are activated by estrogen and inhibit female sexual receptivity. The initial estrogen-induced sexual nonreceptivity is correlated with the activation and internalization of mu-opioid receptors (MORs), in the medial preoptic nucleus (MPN). Progesterone reverses the estrogen-induced activation/internalization of MOR and induces the sexual receptive behavior lordosis. To determine whether NPY and endogenous opioids interact, we tested the hypothesis that estrogen-induced MOR activation is mediated through NPY-Y1 receptor (Y1R) activation. Retrograde tract tracing demonstrated Y1Ron beta-END neurons that projected to the MPN. Sex steroid modulation of MOR in the MPN acts through NPY and the Y1R. Estradiol administration or intracerebroventricular injection of NPY activated/internalized Y1R in the arcuate nucleus and MOR in the MPN of ovariectomized (OVX) rats. Moreover, the selective Y1R agonist [Leu31, Pro34]-Neuropeptide Y (LPNY) internalized MOR in the MPN of OVX rats. The Y1R antagonist (Cys31, Nva34)-Neuropeptide Y (27-36)2 prevented estrogen-induced Y1R and MOR activation/internalization. NPY reversed the progesterone blockade of estradiol-induced Y1R and MOR internalization in the arcuate nucleus and MPN, respectively. Behaviorally, LPNY inhibited estrogen plus progesterone-induced lordosis, and the MOR-selective antagonist D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr amide reversed LPNY-induced inhibition of lordosis. These results suggest that a sequential sex steroid activation of NPY and MOR circuits regulates sexual receptivity.
Mills
Richard H
RH
Department of Neurobiology, David Geffen School of Medicine, Laboratory of Neuroendocrinology, Brain Research Institute, University of California, Los Angeles, California 90095, USA. rmills@usuhs.mil
Sohn
Richard K
RK
Micevych
Paul E
PE
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009478:Neuropeptide Y / Q000031:analogs & derivatives* / Q000494:pharmacology; D010052:Ovariectomy; D011187:Posture / Q000502:physiology; D011301:Preoptic Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017476:Receptors, Neuropeptide Y / Q000819:agonists / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism*; D012726:Sexual Behavior, Animal / Q000187:drug effects / Q000502:physiology; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology
D004967:Estrogens; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D017450:Receptors, Opioid, mu; C097212:neuropeptide Y-Y1 receptor; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; C062259:neuropeptide Y, Leu(31)-Pro(34)-; D011374:Progesterone; D004958:Estradiol; D013004:Somatostatin