Cranial
hypersensitivity is a prominent symptom of
migraine, exhibited as
migraine headache exacerbated with physical activity, and cutaneous facial
allodynia and
hyperalgesia. The underlying mechanism is believed to be, in part, activation and sensitization of dural-responsive trigeminocervical neurons. Validated preclinical models that exhibit this phenotype have great utility for understanding putative mechanisms and as a tool to screen
therapeutics. We have previously shown that
nitroglycerin triggers cranial
allodynia in association with
migraine-like
headache, and this translates to neuronal cranial
hypersensitivity in rats. Furthermore, responses in both humans and rats are aborted by
triptan administration, similar to responses in spontaneous
migraine. Here, our objective was to study the
nitroglycerin model examining the effects on therapeutic targets with newly approved treatments, specifically
gepants and ditans, for the acute treatment of
migraine. Using electrophysiological methods, we determined changes to ongoing firing and somatosensory-evoked cranial sensitivity, in response to
nitroglycerin, followed by treatment with a
calcitonin gene-related peptide receptor antagonist,
gepant (
olcegepant), a
5-HT1F receptor agonist, ditan (
LY344864), and an NK1 receptor antagonist (
GR205171).
Nitroglycerin induced activation of
migraine-like central trigeminocervical neurons, and intracranial and extracranial neuronal
hypersensitivity. These responses were aborted by
olcegepant and
LY344864. However,
GR205171, which failed in clinical trial for both abortive and preventive treatment of
migraine, had no effect. These data support the
nitroglycerin model as a valid approach to study cranial
hypersensitivity and putative mechanisms involved in
migraine and as a screen to dissect potentially efficacious
migraine therapeutic targets.