Estrogen receptor‐α is required for estrogen‐induced μ‐opioid receptor internalization

Abstract

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.

Morphine Suppresses Tumor Angiogenesis through a HIF-1α/p38MAPK Pathway

“…34 Thus, it is difficult to determine whether the effect of morphine in the Gupta et al studies 7 resulted from a direct effect of morphine, because the morphine effects were not antagonized by naloxone, the classical opioid antagonist. Interestingly, another study reported that morphine treatment, using the same MCF-7 hormone-dependent breast cancer cells in a mouse tumor model, increased tumor cell apoptosis through a p53 pathway to inhibit tumor growth.…”

“…During hypoxia, p38 MAPK is activated as an early response to hypoxia [33][34] and inhibition of p38 activity, through genetic 22 or pharmacological manipulation, 35 suppresses HIF-1␣ accumulation. Depending on the cell type, p38 activation is necessary for HIF-1␣ phosphorylation as it reduces the ability to bind VHL and thus prevent proteosomal degradation and promote HIF-1 stabilization.…”

Morphine preferentially activates the periaqueductal gray–rostral ventromedial medullary pathway in the male rat: A potential mechanism for sex differences in antinociception

“…Alternatively, as the gene encoding Fos contains an estrogen response element (Loose-Mitchell et al, 1988,Wang et al, 2003, changes in cycle status may have potentially influenced the ability of morphine to induce Fos in PAG-RVM neurons in females. Lastly, estradiol has also been shown to induce MOR internalization (Eckersell et al, 1998,Sinchak and Micevych, 2001,Micevych et al, 2003,Mills et al, 2004; this would limit the amount of receptor available …”

Association of the mu-opioid receptor gene with smoking cessation

“…Several preclinical studies have indicated sex differences in opiate discrimination, self-administration and reward, [36][37][38] whereas sex has been reported to influence mu-opioid receptor binding in the human brain, 39 possibly mediated via differences in oestrogen-induced regulation. 40,41 More recently, the OPRM1 gene has been reported to be associated with the relative reinforcing value of nicotine in women, but not in men. 42 One common fear, particularly among women, which can deter smokers from attempting to quit is the potential of weight gain following cessation.…”