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ABSTRACTIntroductionCalcitonin gene-related peptide (CGRP) is a vasodilatory neuropeptide involved in the pathophysiology of migraine, a highly disabling neurovascular disorder characterized by severe headache attacks. Rimegepant is a small-molecule CGRP receptor antagonist approved by the FDA for acute treatment of migraine and currently under investigation for migraine prophylaxis. Areas coveredThe authors summarize available data on safety and tolerability of rimegepant and provide insights on its use for acute migraine treatment. Expert opinionRimegepant seems to be well tolerated and superior to placebo for two-hour pain freedom. Moreover, rimegepant does not induce vasoconstriction, and is therefore not contraindicated in patients with cardiovascular disease, nor does it seem to induce medication-overuse headache. However, the therapeutic gain of rimegepant is only small, and since CGRP is a vital rescue molecule during ischemia, blocking the CGRP pathway might be detrimental. Although current evidence on CGRP receptor blockade has shown no cardiovascular adverse events, clinicians should remain critical about the use of rimegepant, as well as other CGRP (receptor)-inhibiting drugs. Further research should focus on determining the consequences of long-term CGRP blockade, especially during ischemia or cardiovascular disease, the exact receptors antagonized by rimegepant, and potential effects of combining rimegepant with other antimigraine treatments.

The hypothalamic-pituitary-adrenal axis involves timed signaling between the hypothalamus, pituitary, and adrenal glands and back to the brain, causing an inherently oscillating system. Corticosteroids such as corticosterone (CORT) are secreted in a circadian rhythm, characterized by low and high levels at the start of the inactive and active phases, respectively. The circadian rhythm overarches ultradian CORT pulses, with approximate 1-hour interpulse intervals. We examined the physiological relevance of pulsatile CORT exposure for neurons of the basolateral amygdala (BLA), an area important for fear learning. We first applied four pulses of equal, high CORT concentration and measured the frequency of miniature excitatory postsynaptic currents (mEPSCs) reflecting spontaneous glutamate signaling. BLA neurons responded differently to each pulse, showing "metaplasticity," extending earlier studies. Next, we mimicked the progression of the inactive and active phases by four CORT pulses of increasing and decreasing concentrations, respectively. CORT pulses of increasing concentration were necessary and sufficient to gradually increase baseline (between-pulse) mEPSC frequency during the mimicked inactive phase, whereas the opposite was seen with decreasing CORT levels during the mimicked active phase. To study the relevance of changed glutamate transmission on behavior, mice were tested in tone-cued fear conditioning during the active or inactive phase. Animals tested at the inactive compared with the active phase showed efficient fear learning; this was also observed when animals tested during the active phase were treated with the CORT synthesis blocker metyrapone. This suggests that natural CORT rhythms influence electrical activity in the BLA, possibly contributing to altered behavioral function.