Dural afferents express acid-sensing ion channels: a role for decreased meningeal pH in migraine headache.
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 20nA 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 constant of pH 6.0-evoked currents in the majority of dural afferents was less than 500ms 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.
University of Arizona School of Medicine, Department of Pharmacology, 1501 N Campbell Ave., Life Science North Room 648, Tucson, AZ 85724, USA.
Jin
J
Yan
Rebecca M
RM
Edelmayer
Xiaomei
X
Wei
Milena
M
De Felice
Frank
F
Porreca
Gregory
G
Dussor
D062565:Acid Sensing Ion Channels; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000344:Afferent Pathways / Q000502:physiology; D000584:Amiloride / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D004388:Dura Mater / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D008297:Male; D008578:Meninges / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism*; D013266:Stilbamidines / Q000378:metabolism; D013268:Stimulation, Chemical; D012668:Trigeminal Ganglion / Q000166:cytology
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D009419:Nerve Tissue Proteins; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013266:Stilbamidines; D000584:Amiloride