title: 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.
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC San Juan de Alicante, Avenida de la Universidad, s/n, 03202 Alicante, Spain ; Instituto Fernandez Vega, Fundación de Investigación Oftalmológica, Av Doctores Fernández Vega, 34, 33012 Oviedo, Asturias Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Belmonte
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC San Juan de Alicante, Avenida de la Universidad, s/n, 03202 Alicante, Spain.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Acosta
authors.affiliation: Instituto Fernandez Vega, Fundación de Investigación Oftalmológica, Av Doctores Fernández Vega, 34, 33012 Oviedo, Asturias Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Merayo-Lloves
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC San Juan de Alicante, Avenida de la Universidad, s/n, 03202 Alicante, Spain.
authors.forename: Juana
authors.initials: J
authors.lastname: Gallar
keywords: Dry eye; Eye inflammation; Eye pain; Nerve injury; Neuropathic pain; Pathobiological modulation; Peripheral pain mechanisms; Physiological or nociceptive pain; Transduction mechanisms