Hypothalamic orexin’s role in exacerbated cutaneous vasodilation responses to an anxiogenic stimulus in a surgical menopause model

Abstract

Distressing symptoms such as hot flashes and sleep disturbances affect over 70% of women approaching menopause for an average of 4–7 years, and recent large cohort studies have shown that anxiety and stress are strongly associated with more severe and persistent hot flashes and can induce hot flashes. Although high estrogen doses alleviate symptoms, extended use increases health risks, and current non-hormonal therapies are marginally better than placebo. The lack of effective non-hormonal treatments is largely due to the limited understanding of the mechanisms that underlie menopausal symptoms. One mechanistic pathway that has not been explored is the wake-promoting orexin neuropeptide system. Orexin is exclusively synthesized in the estrogen receptor rich perifornical hypothalamic region, and has an emerging role in anxiety and thermoregulation. In female rodents, estrogens tonically inhibit expression of orexin, and estrogen replacement normalizes severely elevated central orexin levels in postmenopausal women. Using an ovariectomy menopause model, we demonstrated that an anxiogenic compound elicited exacerbated hot flash-associated increases in tail skin temperature (TST, that is blocked with estrogen), and cellular responses in orexin neurons and efferent targets. Furthermore, systemic administration of centrally active, selective orexin 1 or 2 and dual receptor antagonists attenuated or blocked TST responses, respectively. This included the reformulated Suvorexant, which was recently FDA-approved for treating insomnia. Collectively, our data support the hypothesis that dramatic loss of estrogen tone during menopausal states leads to a hyperactive orexin system that contributes to symptoms such as anxiety, insomnia, and more severe hot flashes. Additionally, orexin receptor antagonists may represent a novel non-hormonal therapy for treating menopausal symptoms, with minimal side effects.

Sexually Dimorphic Changes of Hypocretin (Orexin) in Depression

“…One may thus speculate that the higher levels of hypocretin-1-ir in female patients may enhance depressive symptoms. It should be noted that since all the female subjects studied in our study were in their postmenopausal stage, one would not expect to see the hot flash-related hypocretin changes reported earlier ( Federici et al, 2016 ).…”

Effects of Herbal Mixture Extract on Menopausal Hot Flashes and Pharmacokinetics in Ovariectomized Rat Models

“…Yohimbine, an α 2 -adrenoceptor antagonist, is known to cause hot flashes through the reduction of the thermoneutral zone, which affects temperature homeostasis [30,31]. FG-7142, calcitonin gene-related peptide, and neurokinin B have also been used to trigger hot flashes [32,33,34].…”

Anxiogenic CO2 stimulus elicits exacerbated hot flash-like responses in a rat menopause model and hot flashes in postmenopausal women

“…A weakness of the present rodent studies was that only CO 2 was used as a stressor. However, we recently demonstrated that the GABAergic compound FG-7142 (a partial inverse benzodiazepine receptor agonist) which causes anxiety and flushing clinically (39) elicited rapid hot flash-associated increases in TST in OVEX rats but not sham control rats (40). Other studies have previously documented that stress-related stimuli, including mental arithmetic or emotionally salient films, can increase the rate of objective and subjective hot flashes (12) and self-reports implicate stressful stimuli (e.g.…”

“…Noradrenergic and serotonergic neurons in the midbrain pons and medulla also exhibit hypercapnic responsivity (28). Hypothalamic and brainstem sites including serotonergic nuclei (dorsal raphe and raphe pallidus) and noradrenergic nuclei (locus ceruleus) were found to significantly increase in response to FG-7142 hot flash provocation as well (40). These latter sites may be especially relevant to hot flashes in women because both the noradrenergic and serotonergic systems are treatments for hot flashes with selective serotonin and/or norepinephrine reuptake inhibitors (56, 57).…”