Cold Thermoreceptors, Unexpected Players in Tear Production and Ocular Dryness Sensations

New Developments Cold Thermoreceptors, Unexpected Players in Tear Production and Ocular Dryness Sensations

Carlos Belmonte1,2 and Juana Gallar1

hysical and chemical agents acting on the ocular surface Polymodal nociceptor neurons are the most abundant class P(extreme environmental temperatures, wind, foreign bod- of ocular nociceptor neuron. Polymodal nerve endings are ies, and chemicals) elicit conscious sensations and reflex motor activated tonically by mechanical forces, but they also dis- and autonomic responses (blinking, lacrimation, conjunctival charge repeatedly in response to heat, external irritant chem- vasodilation) aimed at protecting the eye from further injury. icals, and a large variety of endogenous chemical agents re- Sensory nerve terminals of trigeminal ganglion neurons inner- leased by damaged tissues and immune cells (protons, vating the cornea and conjunctiva are the origin of the periph- arachidonic acid metabolites, kinins, cytokines, and growth eral neural information that reaches higher central nervous factors) during injury and inflammation.5–8 A prominent fea- system areas, evoking ultimately these protective neural re- ture of polymodal nociceptor neurons is their functional plas- sponses.1–4 ticity after injury. Their responsiveness changes drastically a The innervation of the eye surface is provided by function- few minutes after tissue damage, that is, they develop sensiti- ally distinct types of trigeminal ganglion neurons, whose pe- zation. Sensitizing polymodal nociceptors develop an irregular, ripheral nerve endings specialize in the preferential detection low-frequency impulse activity long after stimulation has of various modalities of physical (mechanical, thermal) and ceased. Also, the threshold for subsequent stimuli decreases, chemical (exogenous irritants and endogenous mediators) and their responses to new stimuli increases.5,6 Sensitization of stimuli, encoding their spatial and temporal characteristics the polymodal nociceptors that innervate injured and/or in- (intensity and duration) into a discharge of nerve impulses. flamed ocular tissues is the origin of spontaneous pain and of Most ocular trigeminal ganglion neurons belong to the general enhanced pain in response to stimuli at the injured area (pri- group of nociceptor sensory neurons whose peripheral nerve mary hyperalgesia).5 When nociceptor nerve endings are di- endings are activated by injurious or near injurious stimuli that rectly damaged, they may exhibit a reduced responsiveness to 5 initiate normal pain sensations. natural stimuli.9,10 Nonetheless, the injured parent axons still display ongoing activity that causes spontaneous pain referred to the wounded area.5,10 Sustained stimulation and/or destruc- CORNEAL PAIN IS SIGNALED BY MECHANO- AND tion of the terminal part of peripheral nerves additionally POLYMODAL NOCICEPTORS trigger long-term molecular and morphologic changes in the surviving segments of polymodal nociceptor neurons. As a Mechanonociceptor neurons are the fastest conducting of the consequence, membrane excitability and responsiveness to nociceptor neurons that innervate the eye surface. Their pe- peripheral stimuli are altered.10 Knowledge of the molecular ripheral endings are normally recruited only by mechanical substrates responsible for polymodality and plasticity after in- forces and respond to sustained mechanical stimulation with a flammation or nerve damage has progressed in recent years, short burst of nerve impulses at intensities that are compara- leading to the identification of a large number of transducing tively low relative to those that cause injury in other territories and receptor membrane proteins such as TRP channels and such as the skin, but become potentially noxious for the receptor molecules for inflammatory agents, as well as to a fragile, unkeratinized corneal or conjunctival surface epithe- more detailed definition of the intracellular signaling pathways lium. This population of ocular sensory nerve afferents appears and gene expression changes associated with injury.11 to signal primarily mechanical insults to the eye surface and Postinjury modifications of the impulse firing pattern in possibly contributes to the sharp, pricking pain experienced polymodal nociceptors and of their responsiveness to new when a foreign body touches the corneal or conjunctival sur- stimuli are determined by the intensity, type, time course, and face.6,7 duration of the tissue insult. This variability explains in mech- anistic terms the differences in intensity profile and temporal evolution of ocular discomfort and pain sensations that de-

1 velop under pathological conditions involving cell destruction, From the Instituto de Neurociencias de Alicante, Universidad local inflammation, and/or peripheral nerve injury of the eye Miguel Hernańdez-CSIC (Consejo Superior de Investigaciones Científi- 5,9 cas), San Juan de Alicante, Spain; and the 2Fundacioń de Investigacioń surface tissues. As expected from their nociceptive nature, Oftalmolo´gica, Instituto de Oftalmología Fernańdez-Vega, Oviedo, experimental, selective stimulation of the population of cor- Spain. neal polymodal nociceptors in humans evokes stinging and Supported by the Spanish MICINN (Ministerio de Ciencia e Inno- burning pain referred to the eye.12–15 Moreover, drugs that vacioń): projects BFU2008-04425 (CB) and SAF2008-00529 (JG), and interfere with inflammation pathways thereby reducing noci- by Consolider-Ingenio 2010 CSD2007-00023. ceptor sensitization behave as efficacious analgesics. There- Submitted for publication December 23, 2009; revised February 3, fore, it is generally accepted that activity in polymodal nocice- 2011; accepted March 25, 2011. ptors at the ocular surface is the main basis of the pain that Disclosure: C. Belmonte, None; J. Gallar, None Corresponding author: Carlos Belmonte, Instituto de Neurocien- accompanies clinical conditions such as keratitis, corneal ul- cias de Alicante, Universidad Miguel Hernandez-CSIC, Avda. Santiago cers, surgical wounds, contact lens wear, and conjunctivitis. Ramoń y Cajal s/n, 03550 San Juan de Alicante, Spain; Likewise, the prevalent opinion concerning the origin of the [email protected]. unpleasant sensations that accompany dry eye has been that

DOI:10.1167/iovs.09-5119 3888 Investigative Ophthalmology & Visual Science, May 2011, Vol. 52, No. 6 Copyright 0 The Association for Research in Vision and Ophthalmology, Inc.

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they are primarily due to mechanical and/or chemical excita- wild-type animals. This strongly supports the view that under tion of polymodal nociceptors secondary to distortion of nerve normal circumstances, the continuous impulse firing from cold endings by ocular surface desiccation, tear hyperosmolarity, thermoreceptors represents a tonic stimulus for basal tear fluid and/or release of inflammatory mediators into tears.1–3 secretion, conceivably activating at the superior salivary nucleus the parasympathetic secretory drive to the lacrimal glands and goblet cells (Fig. 1).26,27 Moreover, experimental THE CORNEA IS ALSO INNERVATED BY warming of the ocular surface in mice or human subjects—a COLD THERMORECEPTORS maneuver that transiently silences corneal cold thermoreceptors—decreases basal tearing, further confirming in humans Cold thermoreceptors represent a separate class of corneocon- the hypothesis that the basal flow of tears is partly dependent junctival sensory neurons with unique, specific properties. on the tonic input from the peripheral cold thermoreceptor These include spontaneous firing of nerve impulses, often in endings located at the ocular surface.18 bursts, at the normal background temperature of the cornea or The activity of cold thermoreceptors within the normal conjunctiva (34–35°C) and immediate increase of their im- range of corneal temperatures in healthy eyes appears to pulse activity when the corneal temperature drops, which exert a nearly maximal stimulatory effect on tear secretion, thereafter stabilizes gradually at a higher impulse frequency because further increases in cold receptor activity obtained level, proportional to the new value of corneal temperature.16 by larger corneal cooling stimuli within the innocuous level Thus, cold thermoreceptors encode in their firing frequency causes only modest elevations of the basal tearing rate.18 the speed and magnitude of temperature reductions at the However, it is worth noting that the magnitude of the tonic ocular surface as well as the final static temperature. In the excitatory input of cold receptors to central parasympa- normal range of corneal temperatures (36–29°C), cold thermo- thetic neurons possibly depends on the total number of receptors are able to discriminate transient temperature varia- active fibers and their mean firing frequency, as occurs with tions of 0.5°C or less.7,17,18 As expected, psychophysical ex- other secretory and vascular autonomic responses driven by periments using corneal esthesiometry in human subjects have cutaneous thermoreceptor sensory input.28,29 Cold- shown that they are able to discriminate corneal temperature dependent basal tearing is expected to decay if the overall drops of 1°C to 2°C below basal level.14,15 sensory inflow provided by the whole population of ocular The prominent sensitivity of ocular cold receptors to small cold afferent fibers decreases, as presumably occurs when temperature reductions of the eye surface is puzzling. There is cold trigeminal neurons progressively die with aging.30 This no evidence that corneal thermal information is used for envi- mechanism could contribute to the increased incidence of ronmental temperature assessment in animals, including hu- deficient basal tear secretion with age (Fig. 1). mans. In fact, only under precise experimental conditions are While maintenance of basal tear secretion presumably de- humans capable of clearly ascribing a thermal quality to the pends on the tonic activity of cold afferent fibers, sudden in- mildly irritant sensation evoked by moderate cooling of the creases in tear flow produced by injurious or irritant ocular sur- ocular surface.14,19,20 face stimuli are mediated by polymodal nociceptors.31 The effect of polymodal nociceptors appears to be independent of the tonic influence on basal tearing exerted by cold thermoreceptors. Irri- CORNEAL COLD RECEPTORS DETECT OCULAR tation-induced, reflex increases in tear flow remain fully operative Ϫ Ϫ SURFACE WETNESS AND CONTRIBUTE TO in Trpm8 / mice, in which cold fibers are silent.18 BASAL TEARING An alternative and perhaps more relevant role for corneal and COLD THERMORECEPTORS CONTRIBUTE TO conjunctival cold thermoreceptors seems to be providing sen- DRYNESS SENSATIONS sory information about the degree of wetness of the ocular surface.18,21 During the interblink periods, the ocular surface Experimental selective stimulation of corneal cold receptors in temperature, which is approximately 34°C when the eyes are humans by small decreased in temperature (1–3°C) evokes closed, falls gradually, at a rate of 0.3°C/s,22 because of evap- distinct, conscious sensations of cooling that become in- oration. As mentioned above, corneal cold receptor endings creasingly unpleasant when larger temperature decreases exhibit a remarkably high sensitivity for dynamic temperature are applied.14,15 Likewise, in the skin, increasing cooling reductions and are thus able to encode into their background evokes escalating unpleasant cold sensations that correlate firing frequency such small temperature oscillations.17 More- directly with a progressive recruitment of cold receptor over, when eyes remain open for longer times or when corneal fibers.28 Possibly, the neural information provided by ocular evaporation is enhanced, corneal temperature decreases are cold thermoreceptors about the subtle temperature oscilla- more pronounced, increasing substantially cold fiber activity. tions occurring in healthy eyes under normal environmental The exquisite thermal sensitivity of corneal trigeminal neurons conditions remains subconscious. This is actually the case is attributable to the expression of TRPM8, a membrane ion for thermal information provided by skin thermoreceptors channel specifically gated by cold.23–25 Cold trigeminal neu- under comfortable external temperatures.28 However, it can rons of other bodily territories may also express Kv1 potassium be speculated that when a sufficient number of ocular cold

channels, which are responsible for the current IKD that acts as sensory ﬁbers ﬁring at higher frequencies are recruited, a a “brake” against cold excitation24,25 and counteracts the re- conscious sensation of eye dryness of a magnitude propor-

sponsiveness to small temperature drops. However, IKD is tional to the number and firing rate of cold receptor affer- absent in corneal cold thermoreceptors, which explains their ents can be expected (Fig. 1). particularly high sensitivity. Moreover, genetic deletion of According to this hypothesis, sensations of ocular dryness TRPM8 channels in mice renders corneal cold thermoreceptors accompanying the augmented tear evaporation would be the insensitive to temperature reductions and silences their back- ocular counterpart of the sensory experience of unpleasant ground activity, proving that TRPM8 channels are essential for cold elicited by external temperature reductions of the skin. cold signaling in corneal cold afferent fibers.18 A surprising We propose that they are at least in part, evoked by an aug- consequence of TRPM8 elimination is that basal tearing in mented activity at corneal cold receptor fibers caused by an Trpm8Ϫ/Ϫ mice is reduced to almost half compared with enhanced, evaporation-induced ocular surface cooling.23 Ele-

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A Normal Aged Injured Dryness Sensation Fiber Activity 32

Dryness Higher Sensation Brain Centers 34 Tear Flow Temperature (ºC) Temperature

36 B Increased tearing

Pons Parasympathetic Activity Pterygopalatine ganglion Tearing

Medulla Evaporation Trigeminal ganglion Cold Receptor Activity Temperature

Superior Cervical Spinal ganglion Cord ? Sympathetic Activity

FIGURE 1. (A) Hypothetical neural mechanisms involved in the maintenance of basal tearing and production of dryness sensations by cold receptor activity. At comfortable environmental temperature and humidity levels, background nerve impulse activity in cold thermoreceptors may oscillate slightly between blinks, but altogether, it does not represent a sensory input of sufficiently large temporal and spatial dimensions to evoke conscious sensations. However, such cold thermoreceptor activity still serves to maintain a tonic excitatory input to central parasympathetic neurons of the salivary nucleus, which project through the pterygopalatine ganglion to the lacrimal glands and maintain basal tearing. Sympathetic activation may also be involved in the determination of the final composition and volume of tears. (B) The hypothetical mechanisms governing the change in tearing rate and the apparition of conscious dryness sensations during evaporative reductions of corneal surface temperature in young and aged people and in patients with injured corneal sensory nerves consecutive to surgery or to severe eye dryness. Left: in normal individuals at comfortable environmental temperature and humidity levels, activity in corneal cold endings (10% of the total number of corneal nerve endings Ϸ100 /mm2; see Refs. 18,43) stimulates basal tear flow, but does not evoke dryness sensations. Dryness sensations appear when strong cooling elicits higher firing frequencies, although additional increases in basal tear flow are modest; conversely, reduced cooling resulting from low evaporation, decreases cold afferent activity and tearing flow. Middle: in elderly individuals, the total number of endings decreases with age to approximately 50%43; this predictably reduces the total afferent sensory input to parasympathetic centers, thereby decreasing basal tear flow. The elevated evaporation that occurs with a thinner tear film, even under comfortable conditions, produces an augmented impulse activity in the surviving cold fibers that tends to counteract the reduced tearing, but also generates conscious dryness sensations. Decreases or increases in corneal temperature produced by changes in evaporation according to environmental conditions will aggravate or alleviate this state. Right: damaged nerve endings display an abnormal, augmented impulse activity that still serves to maintain relatively intact the cold receptor–dependent basal tear flow but is interpreted by the cerebral cortex as a sensory message of ocular dryness.

vated tear osmolarity levels, which also activate corneal cold gradually increase their activity when the cornea dries,34 sug- thermoreceptors,21 may further contribute to the augmented gesting that nociceptor pathways also contribute to the sen- firing and to the ensuing unpleasant sensation of dryness. In sory inflow that encodes the level of ocular desiccation. It is aged individuals in whom basal tear secretion is reduced, the tempting to speculate that mild sensations of ocular dryness lower number of cold fibers that remain functional presumably are mainly dependent on cold receptor activation, whereas the fire at higher frequency due to faster evaporation32 and evoke contribution of polymodal nociceptors becomes more relevant dryness sensations even though their summated sensory inflow when ocular drying is intense enough to become potentially may be still insufficient to maintain the fraction of the tear flow damaging for corneal and conjunctival epithelial cells. dependent on cold fiber tonic effects on parasympathetic path- Finally, it is worth noting that unpleasant sensations of ways. This interpretation does not exclude the possibility that ocular dryness may also appear after traumatic or inflammatory age-dependent excitability changes in central nervous system damage to corneal sensory nerves, in the absence of concom- neurons33 further contribute to the augmented dryness sensi- itant alterations in tear film composition or volume. Peripheral tivity in elderly people. injury gives rise to an abnormal spontaneous firing in damaged The interpretation that corneal cold thermoreceptors con- sensory nerves.35 This is also the case for corneal sensory tribute to conscious dryness sensations does not exclude a nerves after photorefractive surgery,9 thus suggesting that such participation of corneal and conjunctival polymodal nocicep- aberrant activity is interpreted by the brain as ocular surface tors to the production of unpleasant feelings during ocular dryness.36 Nevertheless, the relative contribution of injured surface dryness. In fact, peripheral nociceptor fibers and their cold- and nociceptor peripheral fibers to this type of dysesthe- higher order neurons of the brain stem trigeminal complex sia is still ignored.

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