Abstract
Migraine is a common disabling neurological condition that is associated with several premonitory symptoms that can occur days before the headache onset. The most commonly reported premonitory symptom is marked fatigue that has been shown to be highly predictive of an ensuing migraine attack. The locus coeruleus (LC) is a key nucleus involved in arousal that has also been shown to impact pain processing. It provides one of the major sources of noradrenaline to the dorsal horn of the spinal cord and neocortex. Given the clinical association between migraine, sleep-wake regulation, and fatigue, we sought to determine whether LC modulation could impact migraine-related phenotypes in several validated preclinical models of migraine. To determine its role in migraine-related pain, we recorded dural nociceptive-evoked responses of neurons in the trigeminocervical complex, which receives trigeminal primary afferents from the durovascular complex. In addition, we explored the susceptibility to cortical spreading depression initiation, the presumed underlying phenomenon of migraine aura. Our experiments reveal a potent role for LC disruption in the differential modulation of migraine-related phenotypes, inhibiting dural-evoked activation of wide dynamic neurons in the trigeminocervical complex while increasing cortical spreading depression susceptibility. This highlights the potential divergent impact of LC disruption in migraine physiology, which may help explain the complex interactions between dysfunctional arousal mechanisms and migraine.
Highlights
Migraine ranks as the 2nd most common cause of years lost to disability globally [10]
Our experiments reveal a potent role for locus coeruleus (LC) dysregulation in the modulation of dural-evoked trigeminovascular activation in the trigeminocervical complex (TCC) and the susceptibility to cortical spreading depression (CSD), the presumed underlying mechanism of migraine aura
Using two different validated preclinical models for migraine, we have identified that LC disruption decreases TCC activation to durovascular nociceptive stimulation
Summary
Migraine ranks as the 2nd most common cause of years lost to disability globally [10]. Despite extensive research and clinical development, there remains a major gap in migraine treatment. The majority of studies have focused on targeting migraine pain [13; 16; 37]; there is an increasing understanding of the importance of premonitory (prodromal) symptoms as the earliest identifiable predictors of an ensuing attack [7; 24]. While the literature on the epidemiology of premonitory symptoms is not entirely resolved, key neurological symptoms such as fatigue have emerged as highly prevalent and highly predictive attack hallmarks [12; 22; 43]. The mechanisms underlying the presence of abnormal fatigue and its relationship with migraine-related nociceptive processing remain enigmatic. We sought to explore the impact of dysregulation of the LC on migraine-related phenotypes in validated preclinical models
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