What Causes Eye Pain?

Abstract

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.

Keywords: Dry eye; Eye inflammation; Eye pain; Nerve injury; Neuropathic pain; Pathobiological modulation; Peripheral pain mechanisms; Physiological or nociceptive pain; Transduction mechanisms.

Fig. 1

Schematic representation of the functional types of sensory neurons innervating the ocular surface and the main types of transducing channels expressed by their peripheral nerve terminals. The specific stimuli activating each neuronal class and the quality of sensations evoked by their activation in represented on the right side of the figure. The qualitative sensations attributed to each functional class of neuron is indicated on the left side. LT Low-threshold cold thermoreceptors, HT high-threshold cold thermoreceptors. Modified from: Belmonte C, Viana F. (Ref. [61])

Fig. 2

Schematic representation of the hypothetical influence of injury and inflammation on sensory terminals of TG neurons innervating the ocular surface. Inflammation activates directly and/or sensitizes polymodal nociceptor fibers, causing inflammatory pain while if these fibers are injured, they produce an abnormal, ectopic ongoing activity evoking neuropathic pain. Nerve injury induces on low-threshold cold thermoreceptors (LT) an abnormally high basal ongoing activity that elicits sensations of dryness with a cooling component; when high-threshold cold thermoreceptors (HT) become spontaneously active, unpleasant or painful dryness sensations are evoked. Contrarily, inflammation alone tends to silence TRPM8-dependent impulse activity in both subtypes of cold thermoreceptors

Fig. 3

Hypothetical effects of contact lenses and eye lens solutions on ocular and lid surface tissues. Mechanical forces, temperature changes and chemical stimulation by exogenous irritants or release of endogenous agents consecutive to cell injury, hypoxia or pH and osmolality changes, will lead to sensory nerve stimulation, damage of nerve terminals and local inflammation. Local inflammation will further activate and sensitize sensory nerve fibers. These will evoke discomfort and pain, reflex effects and neurogenic inflammation