Lifestyle triggers of migraine: Sleep restriction and caffeine lower the threshold for migraine-like responses in rats in a sex-specific manner.

objectiveThis study explores whether sleep restriction (SR) and caffeine intake affect migraine susceptibility by testing if each condition, alone or in combination, precipitates migraine-like responses to subthreshold doses of calcitonin gene-related peptide (CGRP) or pituitary adenylate cyclase-activating polypeptide (PACAP) in male and female rats.

backgroundMigraine is a debilitating neurological syndrome that affects approximately 15% of the global population, with a three-fold higher prevalence in females compared to males. Among the peripheral mechanisms underlying migraine, the release of vasoactive peptides by trigeminal ganglion (TG) neurons, such as CGRP and PACAP, plays a crucial role. Various environmental triggers-including sleep or food deprivation, caffeine intake or withdrawal, stress, and light exposure-have been associated with the onset of migraine attacks; however, the mechanisms by which these factors modulate nociceptive sensitization remain poorly understood.

methodsMale and female Wistar rats were subjected to SR for 6 h daily over 3 consecutive days using the gentle handling method, and the periorbital mechanical allodynia was assessed using von Frey filaments before and after each day of SR. Next, a subthreshold dose of CGRP (38 ng/10 μL) or PACAP (0.1 ng/10 μL) was administered into the TG on the third day of SR to evaluate whether sleep loss enhances susceptibility to migraine-like responses. Finally, two additional experiments were conducted to investigate the influence of caffeine (50 mg/kg, orally) exposure in combination of SR in CGRP and PACAP effects. In all experiments, on day 4 (i.e., 24 h after the last SR), the animals were exposed for 1 h to an aversive light for verification of latent sensitization.

resultsThe results demonstrated that SR alone did not alter the periorbital mechanical threshold in either male or female rats. However, when SR was combined with the administration of CGRP or PACAP at subthreshold doses, a significant periorbital mechanical allodynia developed in female, but not in male rats. The exposure to light in the subsequent day caused a transitory reactivation of mechanical allodynia only in females. In well-rested animals, a 3-day caffeine regimen enabled behaviorally subthreshold doses of CGRP or PACAP to elicit migraine-like responses in females, but not in males. In sleep-restricted animals, combining caffeine with subthreshold doses of CGRP or PACAP rendered males susceptible to migraine-like responses and markedly exacerbated these responses in females, including 1 day later, after light exposure.

conclusionThese findings suggest that SR facilitates trigeminovascular sensitization, promoting migraine-like responses in a sex-specific manner and highlighting caffeine as an enhancer of this interaction. Beyond reinforcing the association between poor sleep and migraine, the data offer new insights into the involvement of the purinergic system and sex differences in migraine pathophysiology.