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: Gerard Callejo, Aida Castellanos, Marta Castany, Arcadi Gual, Carolina Luna, M Carmen Acosta, Juana Gallar, Jonathan P Giblin, Xavier Gasull
• Journal: Pain (Pain) Vol. 156 Issue 3 Pg. 483-495 (Mar 2015) ISSN: 1872-6623 [Electronic] United States
• PMID: 25687542 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-guanidine-4-methylquinazoline
• APETx2 protein, Anthopleura elegantissima
• Acid Sensing Ion Channel Blockers
• Acid Sensing Ion Channels
• Acids
• Cnidarian Venoms
• Guanidines
• Quinazolines
• RNA, Messenger
• RNA, Small Interfering
• Amiloride
• Ovalbumin

Topics

• Acid Sensing Ion Channel Blockers (pharmacology)
• Acid Sensing Ion Channels (genetics, metabolism)
• Acids (toxicity)
• Action Potentials (drug effects)
• Amiloride (pharmacology)
• Animals
• Blinking (drug effects, physiology)
• Cnidarian Venoms (pharmacology)
• Cornea (pathology)
• Disease Models, Animal
• Dry Eye Syndromes (chemically induced, drug therapy)
• Eye (innervation)
• Guanidines (pharmacology)
• Guinea Pigs
• Hydrogen-Ion Concentration
• Male
• Nerve Fibers (physiology)
• Ocular Motility Disorders (etiology)
• Ovalbumin (toxicity)
• Pain (chemically induced, metabolism, pathology)
• Patch-Clamp Techniques
• Quinazolines (pharmacology)
• RNA, Messenger (metabolism)
• RNA, Small Interfering (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Sensory Receptor Cells (drug effects, physiology)
• Statistics, Nonparametric