Dural Afferent Mechanisms of Migraine Pain

Abstract

Compelling evidence indicates that dural afferent sensitization initiates migraine pain. Furthermore, mechanisms of dural afferent sensitization may be unique given that ion channels underlying afferent excitability differ greatly depending on the target of innervation. Triptans, serotonin 1B/1D receptor (5HT1B/1DR) agonists, are selectively used for migraine pain which raises the possibility that their selectivity reflects modulation of unique mechanisms of dural afferent sensitization. The specific hypotheses tested in my thesis were that: 1) triptan selectivity reflects differential 5HT1DR distribution, 2) dural afferents have unique electrophysiological properties, and 3) triptan selectivity reflects modulation of these unique properties. Female Sprague Dawley rats were used for all experiments. The density of 5HT1DR was quantified with Western blot and localized with immunohistochemistry. Acutely dissociated dural afferents were examined using patch clamp recordings and compared to temporalis muscle afferents (TM) in the absence and presence of inflammatory mediators (IM): (μM) prostaglandin E2 (1), bradykinin (10), and histamine (1); and sumatriptan. There were four major observations in this thesis : 1) The 5HT1DR is differentially distributed in nerve fibers innervating peripheral tissues such that the density is highest in tissues known to produce migraine-like pain (i.e. circle of Willis and dura) than in structures in which triptans have no efficacy (i.e. TM), 2) dural afferents have marked differences in the ion channel mechanisms mediating passive and active electrophysiological properties in the absence and presence of IM including an increase in Na+ current, a decrease in Ca2+-dependent K+ current, a decrease in voltage gated Ca2+ current, and an increase in Ca2+ dependent Cl- current, and 3) prolonged sumatriptan incubation with 1µM sumatriptan prevented dural afferent sensitization via K+ current modulation. Taken together, the importance of dural afferent signaling in migraine pathogenesis provide a rationale utilizing ionic mechanisms involved in dural afferent sensitization as targets of novel anti-migraine therapies.