To explore changes in corneal sensitivity that develop in patients with dry eye and the relationship between sensibility and severity of the dry eye disease. Experiments were performed in 44 patients with dry eye and 42 healthy individuals. Corneal sensitivity was measured with the Belmonte noncontact gas esthesiometer. Mechanical (air jets at flow rates from 0 to 200 mL/min, reaching the corneal surface at 34 degrees C), thermal (cold or warm air at subthreshold flow rates changing corneal basal temperature +/-1 degrees C), and chemical stimuli (air containing 0% to 50% CO2 at subthreshold flow rate and temperature at the cornea of 34 degrees C) were applied to the center of the cornea to determine the sensitivity threshold for each stimulus modality. The clinical state of the ocular surface was also explored, measuring the fluorescein tear break-up time, the degree of corneal staining with fluorescein and Lissamine green, and tear production with the Schirmer test. Both in control subjects and patients with dry eye, the corneal thresholds for mechanical, chemical, and thermal stimulation increased with age. Moreover, the thresholds for the three modalities of stimuli were significantly higher in patients with dry eye than in control subjects. In both groups, individual mechanical, chemical, and thermal thresholds correlated significantly. Also, high thresholds in patients with dry eye correlated with the intensity of fluorescein and Lissamine green corneal staining but not with the results of the Schirmer test. Patients with dry eye exhibit corneal hypoesthesia after mechanical, thermal, and chemical stimulation that appears to be related to damage to the corneal sensory innervation.

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.