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Papers of the Week


Papers: 14 Sep 2019 - 20 Sep 2019


Animal Studies, Pharmacology/Drug Development

PAIN TYPE:
Migraine/Headache


2019 Sep 18


Nat Commun


10


1

Editor's Pick

Maladaptive activation of Nav1.9 channels by nitric oxide causes triptan-induced medication overuse headache.

Authors

Bonnet C, Hao J, Osorio N, Donnet A, Penalba V, Ruel J, Delmas P
Nat Commun. 2019 Sep 18; 10(1):4253.
PMID: 31534133.

Abstract

Medication-overuse headaches (MOH) occur with both over-the-counter and pain-relief medicines, including paracetamol, opioids and combination analgesics. The mechanisms that lead to MOH are still uncertain. Here, we show that abnormal activation of Nav1.9 channels by Nitric Oxide (NO) is responsible for MOH induced by triptan migraine medicine. Deletion of the Scn11a gene in MOH mice abrogates NO-mediated symptoms, including cephalic and extracephalic allodynia, photophobia and phonophobia. NO strongly activates Nav1.9 in dural afferent neurons from MOH but not normal mice. Abnormal activation of Nav1.9 triggers CGRP secretion, causing artery dilatation and degranulation of mast cells. In turn, released mast cell mediators potentiates Nav1.9 in meningeal nociceptors, exacerbating inflammation and pain signal. Analysis of signaling networks indicates that PKA is downregulated in trigeminal neurons from MOH mice, relieving its inhibitory action on NO-Nav1.9 coupling. Thus, anomalous activation of Nav1.9 channels by NO, as a result of chronic medication, promotes MOH.