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Discomfort in dry eye is possibly caused by an augmented ongoing activity in corneal cold neurons secondary to dryness-induced alterations in sodium and potassium channel expression.

Peripheral neural mechanisms underlying the sensations of irritation, discomfort, and itch accompanying the eye allergic response have not been hitherto analyzed. We explored this question recording the changes in the electrical activity of corneoconjunctival sensory nerve fibers of the guinea pig after an ocular allergic challenge. Sensitization was produced by i.p. ovalbumin followed by repeated application in the eye of 10% ovalbumin on days 14 to 18. Blinking and tearing rate were measured. Spontaneous and stimulus-evoked (mechanical, thermal, chemical) impulse activity was recorded from mechanonociceptor, polymodal nociceptor and cold corneoscleral sensory afferent fibers. After a single (day 14) or repeated daily exposures to the allergen during the following 3 to 4days, tearing and blinking rate increased significantly. Also, sensitization was observed in mechanonociceptors (transient reduction of mechanical threshold only on day 14) and in polymodal nociceptors (sustained enhancement of the impulse response to acidic stimulation). In contrast, cold thermoreceptors showed a significant decrease in basal ongoing activity and in the response to cooling. Treatment with the TRPV1 and TRPA1 blockers capsazepine and HC-030031 reversed the augmented blinking. Only capsazepine attenuated tearing rate increase and sensitization of the polymodal nociceptors response to CO2. Capsazepine also prevented the decrease in cold thermoreceptor activity caused by the allergic challenge. We conclude that changes in nerve impulse activity accompanying the ocular allergic response, primarily mediated by activation of nociceptor's TRPV1 and to a lesser degree by activation of TRPA1 channels, explain the eye discomfort sensations accompanying allergic episodes.

Reflex tear secretion caused by corneal stimulation seems to be chiefly due to activation of corneal polymodal nociceptors, whereas selective excitation of corneal mechanonociceptors or cold receptors appears to be less effective in evoking an augmented lacrimal secretion. Conjunctival receptors stimulated at equivalent levels do not evoke an increased tear secretion.

Sensitization of nociceptor and depression of cold thermoreceptor activity following UV radiation appear to result from an action of inflammatory mediators on TRP channels selectively expressed by sensory nerve terminals. Changes in nerve activity possibly underlie discomfort sensations associated with corneo-conjunctival inflammation induced by UV exposure.

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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.

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