Nitroglycerine triggers triptan-responsive cranial allodynia and trigeminal neuronal hypersensitivity

Abstract

See De Icco and Tassorelli (doi:) for a scientific commentary on this article.There are limited experimental approaches to study cranial allodynia in migraine. Akerman et al. report that nitroglycerine triggers cranial allodynia alongside migraine-like headache in patients, and dural-intracranial trigeminal neuronal hypersensitivity in rats, with both responding to abortive treatments. Using nitroglycerine thus represents a reliable translational approach to study allodynia in migraine.

Acid‐sensing ion channel 3 blockade inhibits durovascular and nitric oxide‐mediated trigeminal pain

“…Further, APETx2 inhibits nitroglycerin and bright light stress‐evoked cutaneous allodynia in nitroglycerin‐naïve and nitroglycerin ‐primed mice, respectively. Given the ability of NO donors such as nitroglycerin to trigger migraine attacks reliably in patients (Ashina et al, ) and cutaneous allodynia/trigeminal sensitisation in rodents (Akerman et al, ; Bates et al, ), our data suggest that this NO‐mediated effect may be at least in part be ASIC3‐dependent. ASIC3 is expressed on trigeminal ganglion neurons (Ichikawa & Sugimoto, ) and dural afferents (Yan et al, ), and its activation by decreased pH leads to elevated CGRP release (Durham & Masterson, ).…”

“…Migraine is a severe disabling brain disorder (Stovner et al, ) characterised by bouts of unilateral pain resulting from activation of trigeminal sensory neurons and sensitisation of nociceptive processing (Goadsby et al, ). Preclinically, NO donors induce a delayed cutaneous allodynia‐like phenotype in rodents (Bates et al, ) in conjunction with increased trigeminal neuronal activity and hypersensitivity to intracranial and extracranial sensory stimulation (Akerman et al, ). Clinically, exposure to nitroglycerin (NTG) an “NO donor” produces a transient headache (Ashina, Hansen, á Dunga, & Olesen, ) and the occurrence of migraine premonitory symptoms in healthy volunteers (Afridi, Kaube, & Goadsby, ).…”

“…Clinically, exposure to nitroglycerin (NTG) an “NO donor” produces a transient headache (Ashina, Hansen, á Dunga, & Olesen, ) and the occurrence of migraine premonitory symptoms in healthy volunteers (Afridi, Kaube, & Goadsby, ). In migraineurs, it produces delayed migraine‐like attacks (Ashina et al, ) and triptan‐responsive cranial allodynia (Akerman et al, ) . While vasodilation may contribute to the acute headache, alternate mechanisms are likely to be involved in the delayed migraine‐like attacks (Marone et al, ).…”

No Gastrointestinal Dysmotility in Transgenic Mouse Models of Migraine

“…While many patients with CADASIL, 50 FASP (unpublished observations), and FHM1 51 experience nausea and/or vomiting with attacks, such symptoms may not arise from or be associated with gastroparesis. 56 Previous studies in rats demonstrated an increase in spontaneous trigeminal neuronal firing, trigeminal neuronal hypersensitivity, 57 and cFos and calmodulin-dependent protein kinase II (CamKII) activation 4 hours after subcutaneous NTG administration. Third, other modifiers of gastrointestinal motility may be critical in the expression of its pathophysiology, such as epigenetic factors 53 or altered microbiome 54 that may require a specific type of exposure to which the mutant mice have not been exposed.…”

“…We did not independently confirm the subcutaneous NTG induction protocol leads to similar findings as observed in mice with intraperitoneal NTG injections (eg, mechanical and thermal hyperalgesia or cFos-activation in the trigeminal nucleus caudalis). 56 Previous studies in rats demonstrated an increase in spontaneous trigeminal neuronal firing, trigeminal neuronal hypersensitivity, 57 and cFos and calmodulin-dependent protein kinase II (CamKII) activation 4 hours after subcutaneous NTG administration. [58][59][60][61] Finally, the ability of nitric oxide to induce migraine attacks in humans with FHM1 is an unsettled question.…”