Abstract
Protons reaching the eyeball from exogenous acidic substances or released from damaged cells during inflammation, immune cells, after tissue injury or during chronic ophthalmic conditions, activate or modulate ion channels present in sensory nerve fibers that innervate the ocular anterior surface. Their identification as well as their role during disease 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. Among the ion channels expressed in trigeminal nociceptors innervating the anterior surface of the eye (cornea and conjunctiva) and annex ocular structures (eyelids), members of the TRP and ASIC families play a critical role in ocular acidic pain. Low pH (pH 6) activates TRPV1, a polymodal ion channel also activated by heat, capsaicin and hyperosmolar conditions. ASIC1, ASIC3 and heteromeric ASIC1/ASIC3 channels present in ocular nerve terminals are activated at pH 7.2–6.5, inducing pain by moderate acidifications of the ocular surface. These channels, together with TRPA1, are involved in acute ocular pain, as well as in painful sensations during allergic keratoconjunctivitis or other ophthalmic conditions, as blocking or reducing channel expression ameliorates ocular pain. TRPV1, TRPA1 and other ion channels are also present in corneal and conjunctival cells, promoting inflammation of the ocular surface after injury. In addition to the above-mentioned ion channels, members of the K2P and P2X ion channel families are also expressed in trigeminal neurons, however, their role in ocular pain remains unclear to date. In this report, these and other ion channels and receptors involved in acid sensing during ocular pathologies and pain are reviewed.
Highlights
Physical and chemical stimuli from the environment are sensed by sensory nerve terminals present in the cornea and conjunctiva
Despite the studies in trigeminal ganglion neurons, and like PS-G protein-coupled receptors (GPCRs), there is a lack of specific studies on purinergic receptors in the sensory nerve endings innervating the anterior part of the eye the role of protons modulating purinergic signaling remains to be properly studied
TRPV1 activation leads to an increase in intracellular calcium that induces inflammatory cytokine release through MAPK signaling (Zhang et al, 2007), it appears that TRPV1 has a significant role in infiltration of inflammatory mediators in the corneal epithelium and stroma
Summary
Physical and chemical stimuli from the environment are sensed by sensory nerve terminals present in the cornea and conjunctiva. Whereas the cornea lies in front of the iris and pupil, the conjunctiva covers the posterior part of the eyelids (palpebral conjunctiva) towards the conjunctival fornix and continues with the anterior part of the sclera until the corneoscleral limbus (bulbar conjunctiva) Both structures are the first line of defense against potential damaging stimuli of the inner eye structures and are covered by a tear film that moistures and lubricates the anterior ocular surface avoiding damage of the corneal epithelium. Ophthalmic drugs used as eyedrops are formulated in acidic solutions to be able to solubilize or stabilize the active compound All these acidic stimuli activate different mechanisms in the ocular surface, mostly ion channels activated by protons in peripheral sensory nerves, which detect and transduce these stimuli to higher brain areas to evoke painful sensations and to induce protective responses. The mechanisms involved in proton sensing in these ocular structures are reviewed in this report
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