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

Caroline Bonnet,Patrick Delmas,Anne Donnet,Jérôme Ruel,Nancy Osorio,Jizhe Hao,Virginie Penalba

doi:10.1038/s41467-019-12197-3

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.

Highlights

Medication-overuse headaches (MOH) occur with both over-the-counter and pain-relief medicines, including paracetamol, opioids and combination analgesics
To probe molecular mechanisms that lead to MOH, we developed a MOH mouse model based on the sustained administration of sumatriptan, a 5-HT receptor agonist selective for 5HT1D and 5-HT1B subtypes
Dual-labeling showed that 89% (n = 124/139) and 91% (n = 101) of peripherin-positive meningeal fibers were immunoreactive for Nav1.9 and calcitonin gene-related peptide (CGRP), respectively (Fig. 1c, d), suggesting that Nav1.9 and CGRP co-distribute in a large proportion of meningeal fibers

Summary

Introduction

Medication-overuse headaches (MOH) occur with both over-the-counter and pain-relief medicines, including paracetamol, opioids and combination analgesics. We show that abnormal activation of Nav1.9 channels by Nitric Oxide (NO) is responsible for MOH induced by triptan migraine medicine. Chronic use of opioids and triptans in animals has been shown to increase the level of calcitonin gene-related peptide (CGRP), which is involved in neurogenic inflammation and headache pain[8,9]. These animals develop a persistent hypersensitivity or latent sensitization to provocative triggers, such as environmental stress stimulus and the well-known human migraine trigger nitric oxide (NO). This latent sensitization persists long after discontinuation of drug administration and produce a state of generalized cutaneous allodynia that was detected in periorbital regions and hind paw

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Conclusion