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Basal tearing is crucial to maintaining ocular surface wetness. Corneal cold thermoreceptors sense small oscillations in ambient temperature and change their discharge accordingly. Deletion of the cold-transducing ion channel Transient receptor potential cation channel subfamily M member 8 (TRPM8) in mice abrogates cold responsiveness and reduces basal tearing without affecting nociceptor-mediated irritative tearing. Warming of the cornea in humans also decreases tearing rate. These findings indicate that TRPM8-dependent impulse activity in corneal cold receptors contributes to regulating basal tear flow.

SUMMARY1. In the cat anaesthetized with sodium pentobarbitone, electrical activity was recorded from single unmyelinated sensory fibres innervating the cornea.2. Based on their response to mechanical (calibrated aesthesiometer), chemical (10 mm acetic acid or 616 mm NaCl) and thermal (cooling from 35 to 5°C; heating to 51°C) stimuli, corneal unmyelinated fibres were classified as polymodal (71 %) or 'cold' nociceptors (29 %).3. Polymodal units responded to mechanical indentation of the cornea and developed fatigue after repeated stimulation. They were excited by temperatures over 37°C and exhibited sensitization to repeated heating.4. Corneal polymodal units were also activated by topical application of 10 mM acetic acid and hypertonic NaCl (616 mM). Capsaicin (0 33 mM) elicited a discharge of impulses that was followed by inactivation to mechanical, chemical and thermal stimuli.5. 'Cold' nociceptors had small receptive fields, preferentially located at the periphery of the cornea. They were excited by small temperature decreases of the corneal surface in a range between 30 and 8°C, but were not responsive to noxious heat.6. 'Cold' nociceptors encoded temperature changes between 35 and 23 'C. The discharge was proportional to the velocity of the temperature drop; sustained temperatures were not signalled by changes in static frequency values. 'Cold' nociceptive fibres responded to hypertonic NaCl (616 mM) and weakly to 10 mM acetic acid. Capsaicin (0 33 mM) first excited and then inactivated 'cold' nociceptors.7. Thermoreceptive fibres were found in the episclera. They fired in bursts and responded to small temperature decreases, but were insensitive to irritant chemicals and capsaicin.

SUMMARY1. Single-unit electrical activity was recorded from thin myelinated sensory nerve fibres innervating the cornea of deeply anaesthetized cats.2. Based on their responses to mechanical (calibrated von Frey hairs), chemical (10 mM-acetic acid and/or 616 mM-NaCl) and thermal (ice-cold or heat up to 51°C) stimuli, corneal Ad fibres were classified as polymodal nociceptors (63%), highthreshold mechanoceptors (22%) and mechano-heat nociceptors (15%). Thin myelinated fibres responding only to cold were found in the limbus of the eye.3. Application of 10 mM-acetic acid on the corneal surface for 30 s evoked in polymodal fibres a brisk discharge of impulses often followed by a low-frequency impulse activity. NaCl (616 mM) produced a more gradual and sustained firing response.4. The responses of polymodal fibres to acid were proportional to extracellular pH values (pH range: 4 5-6 0). After sensitization to repeated heating, most mechanoheat units developed a sensitivity to acidic stimulation.5. Topical 0 33 mM-capsaicin excited polymodal nociceptors of the cornea; 5 min after capsaicin about 15 % of these fibres were inactivated to all subsequent stimuli. In the rest of the fibres, chemical and thermal sensitivity disappeared after 0 33-3 3 mM-capsaicin, but mechanosensitivity was preserved.6. Corneal mechanoceptors and limbal cold receptors were not affected by capsaicin (up to 33 mM).7. These experiments demonstrate that the cornea of the cat is innervated by polymodal as well as mechanoceptive Ad nociceptors. In polymodal nociceptive fibres, mechanical and chemical sensitivities appear to be subserved by separate transduction mechanisms.

Eye pain is an unpleasant sensory and emotional experience including sensory-discriminative, emotional, cognitive, and behavioral components and supported by distinct, interconnected peripheral and central nervous system elements. Normal or physiological pain results of the stimulation by noxious stimuli of sensory axons of trigeminal ganglion (TG) neurons innervating the eye. These are functionally heterogeneous. Mechano-nociceptors are only excited by noxious mechanical forces. Polymodal nociceptors also respond to heat, exogenous irritants, and endogenous inflammatory mediators, whereas cold thermoreceptors detect moderate temperature changes. Their distinct sensitivity to stimulating forces is determined by the expression of specific classes of ion channels: Piezo2 for mechanical forces, TRPV1 and TRPA1 for heat and chemical agents, and TRPM8 for cold. Pricking pain is evoked by mechano-nociceptors, while polymodal nociceptors are responsible of burning and stinging eye pain; sensations of dryness appear to be mainly evoked by cold thermoreceptors. Mediators released by local inflammation, increase the excitability of eye polymodal nociceptors causing their sensitization and the augmented pain sensations. During chronic inflammation, additional, long-lasting changes in the expression and function of stimulus-transducing and voltage-sensitive ion channels develop, thereby altering polymodal terminal’s excitability and evoking chronic inflammatory pain. When trauma, infections, or metabolic processes directly damage eye nerve terminals, these display aberrant impulse firing due to an abnormal expression of transducing and excitability-modulating ion channels. This malfunction evokes ‘neuropathic pain’ which may also result from abnormal function of higher brain structures where ocular TG neurons project. Eye diseases or ocular surface surgery cause different levels of inflammation and/or nerve injury, which in turn activate sensory fibers of the eye in a variable degree. When inflammation dominates (allergic or actinic kerato-conjunctivitis), polymodal nociceptors are primarily stimulated and sensitized, causing pain. In uncomplicated photorefractive surgery and moderate dry eye, cold thermoreceptors appear to be mainly affected, evoking predominant sensations of unpleasant dryness.