title: Acid-sensing ion channels detect moderate acidifications to induce ocular pain.
abstract: Sensory nerve fibers innervating the ocular anterior surface detect external stimuli producing innocuous and painful sensations. Protons are among the first mediators released by damaged cells during inflammation, tissue injury, or other chronic ophthalmic conditions. We studied whether acid-sensing ion channels (ASICs) are expressed in corneal sensory neurons and their roles in the response to moderate acidifications of the ocular surface and in pathologies producing ocular surface inflammation. Moderate acidic pH (6.6) activated ASIC-like currents in corneal sensory neurons, which were blocked by ASIC1- or ASIC3-specific toxins. Acidic pH depolarizes corneal sensory neurons to fire action potentials, an effect blocked by the ASIC3 inhibitor APETx2. 2-Guanidino-4-methylquinazoline, an ASIC3 agonist, activated a population of corneal polymodal sensory nerve fibers and significantly increased the blinking and tearing rate. The nocifensive behaviors produced by application of either a moderate acidic stimulus or ophthalmic drugs formulated in acidic solution were abolished by ASIC blockers. In a model of allergic keratoconjunctivitis, nocifensive behavior was greatly reduced by ASIC3 blockade, presumably by reducing nociceptor sensitization during the inflammatory process. Our results show that, in addition to the established role of TRPV1, ASICs play a significant role in the detection of acidic insults at the ocular surface. The identification of ASICs in corneal neurons and their alterations during different diseases is critical for the understanding of sensory ocular pathophysiology. They are likely to mediate some of the discomfort sensations accompanying several ophthalmic formulations and may represent novel targets for the development of new therapeutics for ocular pathologies.
authors: Neurophysiology Laboratory, Department of Physiological Sciences I, Medical School, Universitat de Barcelona, Barcelona, Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Department of Ophthalmology, Hospital Vall d'Hebron, Barcelona, Spain Instituto de Neurociencias, Universidad Miguel Hernandez-CSIC, San Juan de Alicante, Spain.
authors: Gerard
authors: G
authors: Callejo
authors: Aida
authors: A
authors: Castellanos
authors: Marta
authors: M
authors: Castany
authors: Arcadi
authors: A
authors: Gual
authors: Carolina
authors: C
authors: Luna
authors: M Carmen
authors: MC
authors: Acosta
authors: Juana
authors: J
authors: Gallar
authors: Jonathan P
authors: JP
authors: Giblin
authors: Xavier
authors: X
authors: Gasull
mesh_terms: D062646:Acid Sensing Ion Channel Blockers / Q000494:pharmacology; D062565:Acid Sensing Ion Channels / Q000235:genetics / Q000378:metabolism*; D000143:Acids / Q000633:toxicity*; D000200:Action Potentials / Q000187:drug effects; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001767:Blinking / Q000187:drug effects / Q000502:physiology; D003064:Cnidarian Venoms / Q000494:pharmacology; D003315:Cornea / Q000473:pathology; D004195:Disease Models, Animal; D015352:Dry Eye Syndromes / Q000139:chemically induced / Q000188:drug therapy; D005123:Eye / Q000294:innervation*; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D008297:Male; D009412:Nerve Fibers / Q000502:physiology; D015835:Ocular Motility Disorders / Q000209:etiology; D010047:Ovalbumin / Q000633:toxicity; D010146:Pain / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D018709:Statistics, Nonparametric
chemical_list: C106067:2-guanidine-4-methylquinazoline; C501880:APETx2 protein, Anthopleura elegantissima; D062646:Acid Sensing Ion Channel Blockers; D062565:Acid Sensing Ion Channels; D000143:Acids; D003064:Cnidarian Venoms; D006146:Guanidines; D011799:Quinazolines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000584:Amiloride; D010047:Ovalbumin