Changes in sensory activity of ocular surface sensory nerves during allergic keratoconjunctivitis

Abstract

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.

Functional Properties of Sensory Nerve Terminals of the Mouse Cornea

“…The percentage of axons of a given modality has been generally calculated based on their presence in extracellular recordings of single nerve fibers dissected from the ciliary nerves at the back of the eye, in anesthetized cats or in excised and superfused guinea pig eyes. 22,33 In both cases, thinly myelinated A-delta mechanosensory fibers tend to be picked up more easily than the unmyelinated (C) fibers that are in most cases polymodal nociceptor and cold fibers. 24,33,36 In contrast, the technique used to record from single corneal nerve terminals in vitro in guinea pig or mouse eyes favors the detection of thin cold thermoreceptor terminals, which display spontaneous activity, are more superficially located, and branch more extensively than polymodal and mechanoreceptor endings, thus producing larger-amplitude NTIs.…”

“…22,33 In both cases, thinly myelinated A-delta mechanosensory fibers tend to be picked up more easily than the unmyelinated (C) fibers that are in most cases polymodal nociceptor and cold fibers. 24,33,36 In contrast, the technique used to record from single corneal nerve terminals in vitro in guinea pig or mouse eyes favors the detection of thin cold thermoreceptor terminals, which display spontaneous activity, are more superficially located, and branch more extensively than polymodal and mechanoreceptor endings, thus producing larger-amplitude NTIs. 17,24,[26][27][28]33,34,39,40 In the present work, we tried to confront this caveat through a systematic sampling of impulse activity at regularly distributed points on the corneal surface, thus reaching theoretically all types of nerve terminals.…”

“…21,24 Still, the short-lasting discharge of NTIs evoked by a sustained pressure in these terminals suggests that they belong to the general class of high-threshold, phasic mechanonociceptive primary sensory neurons also identified in the cornea of the cat and guinea pig. [23][24][25]33,34 The transducing channels conferring mechanosensitivity to these endings have not been identified yet, although expression of the mechanosensory channel Piezo2 41 has been reported in approximately 30% of corneal TG neurons. This Piezo2-positive subpopulation of neurons possesses an immunocytochemical profile very different from canonical cold or …”

“…17,49 A smaller proportion of polymodal terminals was also activated by the TRPA1 channel agonist AITC, which also evokes irritative tearing and blinking when applied to mouse eyes. 17 Nonetheless, the low number of polymodal terminals responding to TRPA1 activation in mice, as also seen in guinea pigs, 33 suggests that TRPA1 channels are not highly expressed in corneal polymodal nociceptor endings.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Although dry eye disease is indolent, it has been associated with sleep disturbances/deprivation and resultant depression. In mice with allergic keratoconjunctivitis, the (nonselective) TRPV1 antagonist capsazepine reduced tearing and blinking (Acosta et al, 2013).…”