17β-estradiol rapidly facilitates lordosis through G protein-coupled estrogen receptor 1 (GPER) via deactivation of medial preoptic nucleus μ-opioid receptors in estradiol primed female rats

Abstract

In female rats sexual receptivity (lordosis) can be induced with either a single large dose of estradiol benzoate (EB), or a priming dose of EB that does not induce sexual receptivity followed by 17β-estradiol (E2). Estradiol priming initially inhibits lordosis through a multi-synaptic circuit originating in the arcuate nucleus of the hypothalamus (ARH) that activates and internalizes μ-opioid receptors (MOR) in medial preoptic nucleus (MPN) neurons. Lordosis is facilitated when MPN MOR are deactivated after the initial estradiol-induced activation. We tested the hypothesis that E2 given 47.5 hours post EB acts rapidly through G protein-coupled estrogen receptor 1 (GPER) in the ARH to deactivate MPN MOR and facilitate lordosis. Ovariectomized Long Evans rats implanted with a third ventricle cannula were primed with 2 μg EB. DMSO control, E2, or G1 (GPER selective agonist) was infused 47.5 hours later, and rats were tested for sexual receptivity. E2 and G1 infusions significantly increased levels of sexual receptivity compared to DMSO controls and pretreatment with G15 (GPER antagonist) blocked the facilitation of sexual receptivity. Brains were processed for MPN MOR immunohistochemistry to measure MPN MOR activation levels. E2 and G1 both significantly reduced MPN MOR activation compared to DMSO controls, while pretreatment with G15 blocked MPN MOR deactivation. In another group of EB treated ovariectomized rats, GPER immunofluorescence positive staining was observed throughout the ARH. Together these data indicate that in the 2 μg EB primed rat, E2 rapidly signals through GPER in the ARH to deactivate MPN MOR and facilitate lordosis.

Orphanin FQ-ORL-1 Regulation of Reproduction and Reproductive Behavior in the Female

“…Like EB-only, we have also found that facilitation of lordosis by the EB + non-esterfied-estradiol requires the activation of ORL-1 (Long et al, 2013(Long et al, , 2014. If EB-primed nonreceptive rats are infused with UFP-101 prior to the non-esterfied-estradiol infusion, then MPN MOP remain activated and sexual receptivity is not facilitated (Long et al, 2013(Long et al, , 2014.…”

“…The onset of sexual receptivity in estradiol-only treated animals is delayed and begins about 48 h after initial estradiol treatment, whereas progesterone can facilitate lordosis if given as early as 20-24 h after EB priming (Boling & Blandau, 1939;Sinchak & Micevych, 2001). A third, less used steroid priming paradigm that also induces maximal levels of sexual receptivity primes first with 2 μg EB followed by 17β-estradiol not conjugated to a benzoate molecule (non-esterfied-estradiol) in the place of progesterone (Long, Serey, Welborn, & Sinchak, 2013;Long, Serey, & Sinchak, 2014;Parsons, Rainbow, Snyder, & McEwen, 1984;Pfaff, Schwartz-Giblin, McCarthy, & Kow, 1994). Interestingly, in this last paradigm, lordosis is facilitated within 30 min of non-esterfied-estradiol treatment, and this nonesterfied-estradiol has been shown to be activating an extranuclear estrogen receptor (ER), G protein-coupled estrogen receptor-1 (GPR30; aka GPER-1; Fig.…”

“…Interestingly, in this last paradigm, lordosis is facilitated within 30 min of non-esterfied-estradiol treatment, and this nonesterfied-estradiol has been shown to be activating an extranuclear estrogen receptor (ER), G protein-coupled estrogen receptor-1 (GPR30; aka GPER-1; Fig. 2) (Filardo et al, 2006;Kuo et al, 2007;Long et al, 2013Long et al, , 2014Smith et al, 2009Smith et al, , 2007. Thus, the ability of these different steroid treatment paradigms to facilitate sexual receptivity indicates that multiple neural pathways may mediate both the induction of sexual receptivity and the LH surge (ovulation) such that the patterns are synchronized to optimize the chances that copulation results in pregnancy.…”

“…1; reviewed in Micevych & Sinchak, 2013;Sinchak & Wagner, 2012). All of the steroid priming paradigms that facilitate lordosis converge to regulate the output of ARH β-endorphin (β-END) neurons that project to the MPN (Borgquist et al, 2013(Borgquist et al, , 2014Cheung & Hammer, 1995;Christensen, Dewing, & Micevych, 2011;Christensen & Micevych, 2012Dewing et al, 2007;Dewing, Christensen, Bondar, & Micevych, 2008;Long, Chhorvann, & Sinchak, 2012;Long et al, 2013Long et al, , 2014Micevych, Rissman, Gustafsson, & Sinchak, 2003;Mills, Sohn, & Micevych, 2004;Sanathara et al, 2011Sanathara et al, , 2014Sinchak et al, 2013;Sinchak & Micevych, 2001;Sinchak, Shahedi, Dewing, & Micevych, 2005; Fig. 1).…”

“…Lordosis is facilitated when ARH β-END neurons are deactivated following EB priming by either subsequent progesterone (EB + P), or non-esterfied-estradiol, or after exposure to a high dose of estradiol for 48 h ( Fig. 1; Eckersell et al, 1998;Long et al, 2013Long et al, , 2014Sinchak & Micevych, 2001). MPN MOP deactivation after estradiol priming is an important step in the facilitation of lordosis (AcostaMartinez & Etgen, 2002;Christensen et al, 2011;Dewing et al, 2007;Eckersell et al, 1998;Kelly, Lagrange, Wagner, & Ronnekleiv, 1999;Sinchak & Micevych, 2001).…”