Dural afferents express acid-sensing ion channels: A role for decreased meningeal pH in migraine headache

Abstract

Migraine headache is one of the most common neurological disorders. The pathological conditions that directly initiate afferent pain signaling are poorly understood. In trigeminal neurons retrogradely labeled from the cranial meninges, we have recorded pH-evoked currents using whole-cell patch-clamp electrophysiology. Approximately 80% of dural afferent neurons responded to a pH 6.0 application with a rapidly activating and rapidly desensitizing ASIC-like current that often exceeded 20 nA in amplitude. Inward currents were observed in response to a wide range of pH values and 30% of the neurons exhibited inward currents at pH 7.1. These currents led to action potentials in 53%, 30% and 7% of the dural afferents at pH 6.8, 6.9 and 7.0, respectively. Small decreases in extracellular pH were also able to generate sustained window currents and sustained membrane depolarizations. Amiloride, a non specific blocker of ASIC channels, inhibited the peak currents evoked upon application of decreased pH while no inhibition was observed upon application of TRPV1 antagonists. The desensitization time constants of pH 6.0-evoked currents in the majority of dural afferents was less than 500 ms which is consistent with that reported for ASIC3 homomeric or heteromeric channels. Finally, application of pH 5.0 synthetic-interstitial fluid to the dura produced significant decreases in facial and hind-paw withdrawal threshold, an effect blocked by amiloride but not TRPV1 antagonists, suggesting that ASIC activation produces migraine-related behavior in vivo. These data provide a cellular mechanism by which decreased pH in the meninges following ischemic or inflammatory events directly excites afferent pain-sensing neurons potentially contributing to migraine headache.

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+Channel

“…Functional changes of several types of ion channels may contribute to an altered state of neuronal 6 excitability of trigeminal afferent neurons innervating the dura (Yan and Dussor, 2014). The majority of rat dural afferents display ASIC currents, which are likely mediated by ASIC3-containing channels (Yan et al, 2011). Application of pH 5 synthetic interstitial fluid to the dura of rats induced facial and hind paw allodynia.…”

“…Application of pH 5 synthetic interstitial fluid to the dura of rats induced facial and hind paw allodynia. Facial allodynia is often associated with migraine (Yan et al, 2011). Amiloride has been reported to inhibit cortical spreading depression in rodents, and improved aura and headache severity in 4 of 7 patients of a small clinical trial (Holland et al, 2012).…”

Increased Asics Expression via the Camkii-CREB Pathway in a Novel Mouse Model of Trigeminal Pain

“…The SIF consisted of 10 mM HEPES, 5 mM KCl, 1 mM MgCl 2 , 2.5 mM CaCl 2 , and 135 mM NaCl (adjusted to pH 7.4). The IS contained 1 mM histamine, serotonin, and bradykinin and 0.1 mM prostaglandin E 2 in pH 7.4 SIF [5, 6]. Sham mice were habituated to the test room and recording cage with the same protocol as the mice in other groups but were not subjected to drug administration.…”

“…However, the composition of IS is complex, as it contains unstable, small peptides that are difficult to store. Yan et al have previously reported a study on acute pH-evoked migraine-related pain behaviour, such as facial and hind paw allodynia [5]. An animal model with repeated activation of the dural nociceptors is needed to identify both new mechanisms of trigeminal pain and important factors involved in the transition from episodic to chronic trigeminal pain.…”

Anatomic Evidence for Information Exchange between Primary Afferent Sensory Neurons Innervating the Anterior Eye Chamber and the Dura Mater in Rat

“…[15][16][17] The rats were deeply anesthetized with 10% chloral hydrate (4 mL/kg) and placed in a stereotaxic apparatus (RWD 68030; RWD Life Science Co., Ltd., Shenzhen, China). The rats were topically anesthetized with 2% lidocaine (0.5 mL), applied to the skin.…”