Increased Sensitivity to CGRP is Associated with Chronification of Migraine and Post-Traumatic Headache in Male and Female Mice

Abstract

Migraine is one of the leading causes of disability affecting approximately 15% of the global population. Some individuals are more susceptible to the chronification of migraine with at least 2.5% of the patient population developing chronic migraine (CM) annually. Chronic headache disorders disproportionally affect women, with migraine occurring two to three times more often than in men and presenting with greater attack frequency and severity. These differences raise the possibility of sex-specific mechanisms contributing to migraine pathophysiology. The success of CGRP targeting therapies for both the acute and preventative treatment of migraine highlight CGRP’s crucial role in migraine pathophysiology. Recent findings have demonstrated that CGRP produces female-selective pain, and additionally, acute migraine treatments targeting this peptide exhibit sex-preferential effectiveness that becomes comparable between sexes in chronic conditions. Men appear to experience less therapeutic benefit from CGRP targeting therapies for acute migraine treatment, despite these treatments providing significant relief for women. However, studies further exploring sexually dimorphic mechanisms and incorporating sex-based analysis remains limited, leaving the influence of biological sex on headache chronification largely unexplored. Preclinical studies further support the clinical observations of CGRP-targeting therapies for CM, demonstrating the essential contribution of CGRP for the chronification of migraine. Interestingly, post-traumatic headache (PTH) from mild traumatic brain injury (mTBI) seems to share biologic features with migraine, however mechanisms are not fully understood. CGRP also appears to contribute to this headache condition, which shares migraine-like features and responds to migraine-specific therapeutics. Although concussive injuries are more frequently reported in men, women tend to experience worse outcomes and are more likely to develop persistent PTH, defined as injury-associated headaches lasting beyond three months. Differences in the physiology of the trigeminovascular system, specifically CGRP signaling within this system, may underlie susceptibility to headache chronification. This research aims to provide insight into the fundamental mechanisms of the sexually dimorphic nociceptive actions of CGRP and its contribution to migraine and migraine-like headaches as disorders evolve to chronic states.