Neural basis of sensation in intact and injured corneas

Abstract

A renewed interest in the characteristics and neural basis of corneal and conjunctival sensations is developing in recent years due to the high incidence of discomfort and altered sensitivity of the cornea following refractive surgery, use of contact lenses and dry eyes. Corneal nerves are functionally heterogeneous: about 20% respond exclusively to noxious mechanical forces (mechano-nociceptors); 70% are additionally excited by extreme temperatures, exogenous irritant chemicals and endogenous inflammatory mediators (polymodal nociceptors), and 10% are cold-sensitive and increase their discharge with moderate cooling of the cornea (cold receptors). Each of these types of sensory fibres contributes distinctly to corneal sensations. Mechano-nociceptors mediate, sharp acute pain produced by touching of the cornea. Polymodal nociceptors elicit the sustained irritation and pain that accompany corneal wounding; cold receptors evoke cooling sensations. Depending on the relative activation by the stimulus of each subpopulation of corneal sensory fibres, different subqualities of irritation and pain sensations are evoked. Corneal sensations can be explored experimentally in humans with a gas esthesiometer that applies controlled mechanical, chemical and thermal stimuli to the corneal surface. When the cornea is wounded, corneal nerves are excited and eventually severed in a variable degree and local inflammation is produced. Activated corneal nerves release neuropeptides (SP, CGRP) that contribute to the inflammatory reaction (neurogenic inflammation). They also become sensitized by local inflammatory mediators, such as prostaglandins or bradykinin and thus exhibit spontaneous activity, lowered threshold and enhanced responses to new stimuli. This leads to spontaneous pain and hyperalgesia. Nerves destroyed by injury soon start to regenerate and form microneuromas that exhibit abnormal responsiveness and spontaneous discharges, due to an altered expression of ion channel proteins in the soma and in regenerating nerve terminals. Presumably, this altered excitability is the origin of the lowered sensitivity and the spontaneous pain, dry eye sensations and other disaesthesias reported in patients following refractive surgery.

Introduction

Ophthalmologists have traditionally paid little attention to the mechanism of pain arising from the eye. Trigeminal nerve injuries, which lead to neuropathic pain referred to the eye, are relatively infrequent and in general handled by neurologists. Some common clinical conditions, such as ocular dryness or conjunctivitis normally proceed with moderate levels of ocular discomfort that are in general considered ‘tolerable’ by the clinician. Intense pain may appear in certain ocular disturbances (keratitis, uveitis, scleritis, optic neuritis, angle-closure glaucoma, endophthalmitis) but often as an acute and transient symptom of the disease. Finally, pain is not a serious complication of modern ocular surgery. As a consequence, the number of experimental studies devoted to clarify the properties and neural basis of ocular sensations is scarce.

However, in recent years, symptoms of ocular discomfort often described as ‘eye dryness’ have been reported with increasing frequency, as the result of repeated exposure to contaminated or air-conditioned environments, contact lens wear and the extended use of new surgical techniques for the correction of refractive defects, such as photorefractive keratectomy (PRK) or laser-assisted in situ keratomileusis (LASIK). This has prompted a renewed interest in the neural mechanisms involved in ocular sensations, looking for a relation between the unpleasant sensations experienced in these clinical conditions and the morphological and functional disturbances in the sensory supply to the anterior segment of the eye.