CGRP Is Critical for Hot Flushes in Ovariectomized Mice

Abstract

Hot flushes are common and troublesome symptoms of menopause. The neuropeptide calcitonin gene-related peptide (CGRP) is increased in plasma during hot flushes but it has not been clear if CGRP is causally involved in the mechanism underpinning the flushes. Here, we examined the effect of interventions with CGRP in a mouse model of hot flushes based on flush-like temperature increases triggered by forced physical activity in ovariectomized mice. Compared to normal mice, ovariectomized mice reacted with an exaggerated, flush-like, temperature increase after physical exercise. This increase was completely blocked by the non-peptide CGRP-antagonist MK-8825 (-0.41 degrees Celsius, 95% CI: -0,83 to 0,012, p < 0.0001) at a dose that had no obvious effects on locomotor activity (50 mg/kg). Further, the flush-like temperature increases were strongly attenuated in ovariectomized mice lacking αCGRP due to a genetic modification. Collectively, our findings suggest that CGRP is an important mediator of experimentally induced hot flushes and they identify CGRP antagonists as promising treatment candidates for women and possibly also men with hot flushes.

Calcitonin gene related peptide α is dispensable for many danger-related motivational responses

“…Since αCGRP was lost also during development in these mice, other compensatory mechanisms might have been activated. However, we have previously shown that the mouse line used have deficits in an animal model for hot flushes 28 . This shows that there is no full and general compensation for the lack of αCGRP in this mouse line, but a lack of compensation regarding one readout does not exclude compensation in another response.…”

Changing levels of sex hormones and calcitonin gene-related peptide (CGRP) during a woman’s life: Implications for the efficacy and safety of novel antimigraine medications

“…A study in mice showed that blocking CGRP reduced flush-like symptoms [26], suggesting that anti-CGRP treatment, antagonists or antibodies, could potentially diminish perimenopausal vasomotor symptoms by stabilizing the CGRP fluctuations. Several studies on the effect of hormonal replacement therapy on CGRP levels have reported that after 3 months of treatment, the plasma concentration of CGRP in postmenopausal women significantly increases to levels similar to healthy fertile women [27,28], suggesting a reduced CGRP secretion after menopause, probably associated to sex hormone deficiency [27].…”

Calcitonin Gene Related Peptide Α Is Dispensable for Many Danger-related Motivational Responses

“…Since the mouse line used has been shown to have deficits in CGRP-dependent responses including hot flushes 27 it is unlikely that compensatory mechanisms can explain the lack of effect in our studies.…”