Review Neural basis of sensation in intact and injured corneas Carlos Belmonte * , M. Carmen Acosta, Juana Gallar Instituto de Neurociencias de Alicante, Universidad Miguel Herna ´ndez–CSIC, Apdo correos 18, 03550 San Juan de Alicante, Spain Received 18 September 2003; accepted 25 September 2003 This paper is dedicated to the memory of David Maurice. As in so many other aspects of corneal research, David realized in the early 1970s the need of new methods and approaches to fully understand the mechanisms of corneal sensitivity, and led one of the first attempts to record electrical activity from corneal nerve fibres ‘in vitro’ (Mark and Maurice, 1977) as well as to study human corneal sensation using different modalities of stimuli (Beuerman et al., 1977). Twenty-five years later, similar techniques are being used routinely to extend our knowledge of the functional properties and roles of corneal sensory receptors in normal and injured corneas with the aim of understanding corneal pain, one of the many scientific problems that excited David’s insatiable curiosity. 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. q 2003 Elsevier Ltd. All rights reserved. Keywords: pain; corneal nerves; ocular surface; sensitivity; conjunctiva; dry eye; corneal inflammation; photorefractive keratectomy; laser-assisted in situ keratomileusis; nerve injury 1. 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, endophthal- mitis) 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 exper- imental studies devoted to clarify the properties and neural basis of ocular sensations is scarce. 0014-4835/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. DOI:10.1016/j.exer.2003.09.023 Experimental Eye Research 78 (2004) 513–525 www.elsevier.com/locate/yexer * Corresponding author. Dr C. Belmonte. Instituto de Neurociencias de Alicante, Universidad Miguel Herna ´ndez–CSIC, Apdo correos 18, 03550 San Juan de Alicante, Spain. E-mail address: carlos.belmonte@umh.es (C. Belmonte).