Low Doses of CGRP Trigger Female-Specific Migraine Response

Globally, migraine is ranked as the second-highest cause of disability and is 2 to 3 times more common in women than in men. Migraine is also the most common cause of disability in women aged 15 to 49, though little is known as to why migraine is more prevalent in women.

Researchers of a recently published study in The Journal of Neuroscience used preclinical behavioral models of migraine to determine that the application of calcitonin gene-related peptide (CGRP) to the dura mater, or the protective outer layer between the skull and the brain, in mice produces triggers pain responses only in females. A similar effect was also seen when CGRP was injected into the paw of the female mouse.

Although the CGRP is well known to play a role in migraine, it remains unclear specifically where in the body CGRP contributes to the headache. Researchers also noted that they have yet to determine whether sex differences exist in the neurobiology of this disorder due to previous CGRP studies typically being conducted in only male animals.

“Acute responses to meningeal CGRP are female-specific and sensitization to CGRP after two-distinct stimuli are also female-specific. These data implicate the dura mater as a primary location of action for CGRP in migraine and suggest that female-specific mechanisms downstream of CGRP receptor activation contribute to the higher prevalence of migraine in women,” wrote the authors.

The dural application of interleukin-6 (IL-6) caused acute responses in males and females but only caused priming to the predetermined threshold dural CGRP of 0.1 in females. Additionally, females were primed to a predetermined subthreshold dose of the NO-donor sodium nitroprusside 0.1mg/kg following dural CGRP.

Though the researchers were able to determine that female mice demonstrated greater anatomical and physiological responses than males, they were unable to determine the cause behind this female-specific response.

“These findings also highlight the need for determining whether new therapeutics have sex-specific mechanisms of action, as selecting the proper sex in clinical trials may be key in demonstrating efficacy,” concluded the authors.

Reference

Avona A, Burgos-Vega C, Burton M, et al. Dural calcitonin gene-related peptide produces female-specific responses in rodent migraine models [published April 8, 2019]. JNeurosci. doi:10.1523/jneurosci.0364-19.2019.