Profile of opioid peptide receptors in GnRH and kisspeptin neurons of female mice and rats

Abstract

Kisspeptin neurons play a critical role in the estradiol feedback effects on gonadotropin-releasing hormone (GnRH) neurons and luteinizing hormone (LH) secretion. Endogenous opioid peptides regulate LH secretion, but the neuroendocrine mechanisms involved remain elusive. We used RNAscope to characterize the expression of kappa (Oprk1)-, mu (Oprm1)-, and delta (Oprd1)-opioid receptors in GnRH (Gnrh1) neurons and kisspeptin neurons of the rostral periventricular area of the third ventricle (Kiss1^RP3V) and arcuate nucleus (Kiss1^ARC) in cycling mice and rats with physiological low (metestrus) and high (proestrus) levels of ovarian steroids. In mice, all opioid receptors were colocalized with Gnrh1, with increased coexpression of Oprk1 on proestrus compared with metestrus. Most Kiss1^RP3V neurons expressed Oprk1, Oprm1, or Oprd1, with no changes seen during the estrous cycle. The three opioid receptors were also expressed in Kiss1^ARC neurons, and the expression of Oprk1 in Kiss1^ARC neurons was reduced on proestrus compared with metestrus. When investigated in cycling rats, Kiss1^ARC neurons displayed the same pattern of Oprk1 variation as in mice. However, whereas the mouse Kiss1^ARC neurons displayed a predominance of Oprk1 expression, all three opioid receptors were similarly expressed in the rat. Our results show that Oprk1 is the main opioid receptor present in Kiss1^ARC neurons of mice but not rats, whereas Oprk1, Oprm1, and Oprd1 are abundantly expressed in mouse Kiss1^RP3V and GnRH neurons. Fluctuations in ovarian steroids are likely to modulate Oprk1 levels in GnRH and Kiss1^ARC neurons during the ovarian cycle, implicating this opioid receptor in the feedback control of LH secretion in female rodents.