UNDERSTANDING THE PATHOPHYSIOLOGY OF MIGRAINE: ACTIVATION AND SENSITIZATION OF DURAL AFFERENTS

Abstract

Migraine is one of the most common neurological disorders. The pathological conditions that initiate and sensitize afferent pain signaling are poorly understood. The goal of this study is to identify the ion channels and signaling proteins underlying activation and sensitization of meningeal nociceptors.In trigeminal neurons retrogradely labeled from the cranial meninges, approximately 80% responded to a pH 6.0 application with a rapidly activating and desensitizing ASIC-like current. Pharmacological experiments and kinetics analysis demonstrated that dural afferent pH-sensitive currents were mediated via activation of ASIC3. In addition, applications of decreased pH solutions were able to excite these neurons and generate action potentials. In awake animals, application of decreased pH solutions to the dura produced dose-dependent facial and hindpaw allodynia, which was also mediated through activation of ASIC3. Accumulating evidence indicates that meningeal inflammation induced sensitization of dural afferents contributes to migraine headache. We have demonstrated here that in the presence of mast cell mediators, dural afferents showed a decreased pH threshold and increased activity in response to pH stimuli both in vivo and in vitro. These data provide a cellular mechanism by which decreased pH in the meninges directly excites afferent pain-sensing neurons potentially contributing to migraine headache. It also indicates that inflammatory events within the meninges could sensitize afferent pain signaling and result in increased sensitivity of dural afferents.Intracranial Interleukin-6 (IL-6) levels have been shown to be elevated during migraine attacks, suggesting that this cytokine may facilitate pain signaling from the meninges. Here we reported that in awake animals, direct application of IL-6 to the dura produced dose-dependent facial and hindpaw allodynia via activation of the ERK signaling pathway. IL-6 application was also able to increase neuronal excitability in a manner consistent with phosphorylation of Nav1.7. These data provide a cellular mechanism by which IL-6 in the meninges causes sensitization of dural afferents therefore contributing to the pathogenesis of migraine.These findings are discussed in relation to how activation and sensitization of primary afferent neurons might initiate migraine pain signaling and how the research included in this dissertation relates to the development of new therapeutic strategies for migraine.