Opioidergic Modulation of N-Methyl-D,L-Aspartic-Acid-Stimulated LH Release in Young Adult but not Older Male Mice

Abstract

Among the neuromodulators of the GnRH neuronal system are the endogenous opioid peptides and the excitatory amino acids. Although the opioid antagonist naloxone (NAL) induces LH secretion in many species, there are no reports of an effect of NAL on LH release in mice. Our previous studies demonstrated that the excitatory amino acid analog N-methyl-D,L-aspartic acid (NMA) stimulates LH release in mice and suggested that NMA-induced LH release is mediated via afferents to GnRH neurons. In the current study, the role of the endogenous opioid system in the regulation of LH release in adult male mice was assessed by testing whether this system is a component of the NMA-stimulated LH response. NAL, its quaternary derivative NAL methiodide (which remains outside of the blood-brain barrier) and saline (SAL) were administered alone and in combination with NMA via intravenous catheters. Although neither opioid antagonist stimulated LH release when administered alone, each significantly potentiated the LH response to NMA in young adult (10- to 14-week-old) male mice (p < 0.01) but not in older (10- to 16-month-old) male mice. The equivalent action of the two ipioid blockers suggested an action outside of the blood-brain barrier. To determine whether opioid blockade altered pituitary sensitivity to GnRH, a dose response for exogenously administered GnRH was first determined, and low and high doses of GnRH were tested in combination with NAL or SAL. Neither treatment was effective in altering the LH response to GnRH, indicating that the action of the opioid antagonists was at a suprapituitary location. Ten- to 16-month-old male mice had significantly greater LH responses to NMA than 10- to 14-week-old male mice (p < 0.01). GnRH challenges indicated that the increased LH secretion to NMA seen in the older males was not due to an increased pituitary sensitivity to GnRH. These findings support the hypothesis that NMA stimulates opioidergic neurons which contribute an inhibitory influence on GnRH secretion at a central location outside of the blood-brain barrier, such as the median eminence, and that inhibitory influences on the GnRH neuronal system diminish with aging.

Neuromodulation of Transplanted Gonadotropin-Releasing Hormone Neurons in Male and Female Hypogonadal Mice with Preoptic Area Brain Grafts1

“…Significant NMA effects, with or without pretreatments, were due to responses in a minority of the male mice. Although opioid blockade alone had no effect on LH secretion, female HPG/POA had significantly greater LH secretory responses to NMA when an opiate antagonist was present, similar to our previous findings in normal mice [22]. In contrast, the relative failure of intact HPG/POA males to react to NMA does not appear to be due to opioid inhibition of GnRH release.…”

“…We had previously shown that older (10-16 mo old) normal male mice were more sensitive than younger males to NMA [22], and further, that their increased LH secretion was not due to altered pituitary sensitivity. Pretreatment with opioid antagonists did not alter responsivity to NMA in these older normal males.…”

“…Although the opiate antagonist naloxone (NAL) increases LH secretion in many species, including gonadally intact male [20] and female [21] rats, it fails to do so in male [22] or female (unpublished results) mice. However, opiate antagonists significantly potentiated NMA-induced LH release in young adult male mice [22], suggesting that NMA triggers the release of inhibitory endogenous opioid peptides.…”

Innervation of Gonadotropin-Releasing Hormone Neurons by Peptidergic Neurons Conveying Circadian or Energy Balance Information in the Mouse

“…It is also clear that the expression of genes encoding POMC, NPY and MCH in the hypothalamus is regulated by energy balance in the mouse [41], [42], and that the products of these genes affect GnRH/LH secretion. β-endorphin has been shown to inhibit LH secretion in a wide variety of species [43], and specifically in mice it has been shown that blockade of μ-opioid receptors with naloxone potentiates LH release, for example when induced by glutamatergic agonists [44]. Likewise, there are a number of studies in rats [45], [46] which demonstrate that blockade of NPY receptors with antagonists elicits LH release.…”

Alzheimer?s disease: the impact of age-related changes in reproductive hormones

“…GnRH receptor is a G-protein-coupled receptor, which is 328 amino acids long, and is necessary for GnRH to initiate the release of gonadotropins from pituitary gonadotropes [32,98]. Although species variation exists in the expression of GnRH receptor in extrapituitary tissues [99], GnRH receptor is present in rodent (see below) and human hippocampus [100].…”