What Causes Eye Pain?

Carlos Belmonte, M Carmen Acosta, Jesus Merayo-Lloves, Juana Gallar, Carlos Belmonte, M Carmen Acosta, Jesus Merayo-Lloves, Juana Gallar

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.

Figures

Fig. 1
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
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
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

References

    1. International Association for the Study of Pain (IASP). IASP Task Force on Taxonomy. 1994, revised. Merskey H, Bogduk N, editors. Seattle: IASP Press; 2011.
    1. •• Belmonte C, Tervo TT. Pain in and around the eye. In: McMahon SB, Koltzenburg M, Tracey I, Turks DC, editors. Wall and Melzack’s textbook of pain. 6th ed., Chapter 60. Philadelphia: Elsevier Saunders; 2013. pp. 843–60. A detailed and recent review of the morphological and functional characteristics of the ocular innervation and basic and clinical information on eye pain.
    1. Apkarian AV, Bushnell MC, Schweinhardt P. Representation of pain in the brain. In: McMahon SB, Koltzenburg M, Tracey I, Turks DC, editors. Wall and Melzack’s textbook of pain. 6th ed., Chapter 8. Philadelphia: Elsevier Saunders; 2013. pp. 111–128.
    1. Mano H, Seymour B. Pain: a distributed brain information network? PLoS Biol. 2015;13:1–4. doi: 10.1371/journal.pbio.1002037.
    1. Sherrington CS. The integrative action of the nervous system. New York: Scribner; 1906.
    1. Belmonte C. Signal transduction in nociceptors: general principles. In: Belmonte C, Cervero F, editors. Neurobiology of nociceptors. Oxford: Oxford University Press; 1996. pp. 243–257.
    1. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139:267–284. doi: 10.1016/j.cell.2009.09.028.
    1. Kobayashi S. Organization of neural systems for aversive information processing: pain, error, and punishment. Front Neurosci. 2012
    1. Belmonte C, Aracil A, Acosta MC, Luna C, Gallar J. Nerves and sensations from the eye surface. Ocul Surf. 2004;2:248–253. doi: 10.1016/S1542-0124(12)70112-X.
    1. Ivanusic JJ, Wood RJ, Brock JA. Sensory and sympathetic innervation of the mouse and guinea pig corneal epithelium. J Comp Neurol. 2013;521:877–893. doi: 10.1002/cne.23207.
    1. •• Belmonte C, Giraldez F. Responses of cat corneal sensory receptors to mechanical and thermal stimulation. J Physiol. 1981;321:355–68. The first description of the functional characteristics of corneal polymodal nociceptors and of their sensitization.
    1. •• Belmonte C, Gallar J, Pozo MA, Rebollo I. Excitation by irritant chemical substances of sensory afferent units in the cat’s cornea. J Physiol. 1991;437:709–25. The first experimental study showing responsiveness of corneo-scleral nociceptors to chemical irritation and the existence of different transducing mechanisms for mechanical stimuli and thermal and chemical stimuli.
    1. •• Gallar J, Pozo MA, Tuckett RP, Belmonte C. Response of sensory units with unmyelinated fibres to mechanical, thermal and chemical stimulation of the cat’s cornea. J Physiol. 1993;468:609–22. The first description of the functional characteristics of cold thermoreceptors in the cornea and sclera and their continuous firing and responsiveness to small corneal temperature changes.
    1. Ruskell GL. The source of nerve fibres of the trabeculae and adjacent structures in monkey eyes. Exp Eye Res. 1976;23:449–459. doi: 10.1016/0014-4835(76)90174-3.
    1. Braun HA, Bade H, Hensel H. Static and dynamic discharge patterns of bursting cold fibers related to hypothetical receptor mechanisms. Pflugers Arch. 1980;386:1–9. doi: 10.1007/BF00584180.
    1. Brock J, McLachlan EM, Belmonte C. Tetrodotoxin-resistant impulses in single nerve terminals signalling pain. J Physiol. 1998;512:211–217. doi: 10.1111/j.1469-7793.1998.211bf.x.
    1. Brock JA, Pianova S, Belmonte C. Differences between nerve terminal impulses of polymodal nociceptors and cold sensory receptors of the guinea-pig cornea. J Physiol. 2001;533:493–501. doi: 10.1111/j.1469-7793.2001.0493a.x.
    1. Iñigo Portugués A, Alcalde I, González-González O, Belmonte C, Merayo-Yoves J. Decreased basal tear in aged mice is linked to morphological and functional changes in corneal sensory nerve fibers. Acta Ophthalmol. 2014;92(s253).
    1. Lippoldt EK, Elmes RR, McCoy DD, Knowlton WM, McKemy DD. Artemin, a glial cell line-derived neurotrophic factor family member, induces TRPM8-dependent cold pain. J Neurosci. 2013;33:12543–12552. doi: 10.1523/JNEUROSCI.5765-12.2013.
    1. •• Acosta MC, Belmonte C, Gallar J. Sensory experiences in humans and single-unit activity in cats evoked by polymodal stimulation of the cornea. J Physiol. 2001;534:511–25. The first description of the different quality of corneal sensations evoked by mechanical, chemical and thermal stimuli in humans and the relationship between corneal sensations and activation of the different populations of corneal sensory fibers.
    1. • Acosta MC, Tan ME, Belmonte C, Gallar J. Sensations evoked by selective mechanical, chemical, and thermal stimulation of the conjunctiva and cornea. Invest Ophthalmol Vis Sci. 2001;42:2063–7. The first description of the lower sensitivity to all modalities of stimuli of the conjunctiva versus the cornea in humans.
    1. Felipe CD, González GG, Gallar J, Belmonte C. Quantification and immunocytochemical characteristics of trigeminal ganglion neurons projecting to the cornea: effect of corneal wounding. Eur J Pain. 1999;3:31–39. doi: 10.1016/S1090-3801(99)90186-6.
    1. Lopez de Armentia M, Cabanes C, Belmonte C. Electrophysiological properties of identified trigeminal ganglion corneal nociceptive neurons. Neuroscience. 2000;101:1109–1115. doi: 10.1016/S0306-4522(00)00440-1.
    1. • Marfurt CF, Echtenkamp SF. Central projections and trigeminal ganglion location of corneal afferent neurons in the monkey, Macaca fascicularis. J Comp Neurol. 1988;272:370–82. An excellent anatomical description of the projections of corneal neurons in the brainstem trigeminal complex.
    1. Martinez S, Belmonte C. C-Fos expression in trigeminal nucleus neurons after chemical irritation of the cornea: reduction by selective blockade of nociceptor chemosensitivity. Exp Brain Res. 1996;109:56–62. doi: 10.1007/BF00228626.
    1. •• Hirata H, Hu JW, Bereiter DA. Responses of medullary dorsal horn neurons to corneal stimulation by CO2 pulses in the rat. J Neurophysiol. 1999;82:2092–107. The first detailed functional description of second-order corneal trigeminal neurons.
    1. •• Hirata H, Okamoto K, Tashiro A, Bereiter DA. A novel class of neurons at the trigeminal subnucleus interpolaris/caudalis transition region monitors ocular surface fluid status and modulates tear production. J Neurosci. 2004;24:4224–32. The first description of the location and properties of specific populations of projection neurons responding to eye wetness changes in the trigeminal nuclear complex of the brainstem.
    1. Aicher SA, Hermes SM, Hegarty DM. Corneal afferents differentially target thalamic- and parabrachial-projecting neurons in spinal trigemina nucleus caudalis. Neuroscience. 2013;232:182–193. doi: 10.1016/j.neuroscience.2012.11.033.
    1. Hirata H, Takeshita S, Hu JW, Bereiter DA. Cornea-responsive medullary dorsal horn neurons: modulation by local opioids and projections to thalamus and brain stem. J Neurophysiol. 2000;84:1050–1061.
    1. Panneton WM, Hsu H, Gan Q. Distinct central representations for sensory fibers innervating either the conjunctiva or cornea of the rat. Exp Eye Res. 2010;90:388–396. doi: 10.1016/j.exer.2009.11.018.
    1. Gonzalez G, Garcia de la Rubia P, Gallar J, Belmonte C. Reduction of capsaicin-induced ocular pain and neurogenic inflammation by calcium antagonists. Invest Ophthalmol Vis Sci. 1993;34:3329–3335.
    1. Handwerker HO. Nociceptors: neurogenic inflammation (Chap. 3) Handb Clin Neurol. 2006;81:23–33. doi: 10.1016/S0072-9752(06)80007-2.
    1. Belmonte C, Gallar J, López-Briones LG, Pozo MA. Polymodality in nociceptive neurons: experimental models of chemotransduction. In: Cellular mechanisms of sensory processing. NATO ASI Series. Berlin: Springer; 1994. p. 87–117.
    1. Handwerker HO, Reeh PW. Nociceptors. Chemosensitivity and sensitization by chemical agents. In: Willis WD Jr, editor. Hyperalgesia and allodynia. New York: Raven Press; 1992. pp. 107–15.
    1. Hucho T, Levine JD. Signaling pathways in sensitization. Toward a nociceptor cell biology. Neuron. 2007;55:366–376. doi: 10.1016/j.neuron.2007.07.008.
    1. Devor M. Response of nerves to injury in relation to neuropathic pain. In: McMahon SB, Koltzenburg M, Tracey I, Turks DC, editors. Wall and Melzack’s textbook of pain. 6th ed., Chapter 58. Philadelphia: Elsevier Saunders; 2013. pp. 905–27.
    1. von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron. 2012;73:638–652. doi: 10.1016/j.neuron.2012.02.008.
    1. • Belmonte C, Brock JA, Viana F. Transforming cold into pain. Exp Brain Res. 2009;196:13–30. A general review of the molecular and biophysical mechanisms underlying peripheral transduction of physical and chemical stimuli, particularly centered in cold transduction and on how low temperatures are discriminated as cold or pain.
    1. •• Bron R, Wood RJ, Brock JA, Ivanusic JJ. Piezo2 expression in corneal afferent neurons. J Comp Neurol. 2014;522:2967–79. The first demonstration of the presence of the mechanosensory channel Piezo 2 in corneal mechanosensory nerve fibers.
    1. Chen X, Belmonte C, Rang HP. Capsaicin and carbon dioxide act by distinct mechanisms on sensory nerve terminals in the cat cornea. Pain. 1997;70:23–29. doi: 10.1016/S0304-3959(96)03256-3.
    1. •• Parra A, Madrid R, Echevarria D, delOlmo S, Morenilla-Palao C, Acosta MC, Gallar J, Dhaka A, Viana F, Belmonte C. Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea. Nat Med. 2010;16:1396–9. The first demonstration that cold thermoreceptors of the cornea depend on the expression of the TRPM8 channel for spontaneous and cold evoked responses and of the role of cold thermoreceptors in the maintaining of basal tearing in rodents and humans.
    1. • Murata Y, Masuko S: Peripheral and central distribution of TRPV1, substance P and CGRP of rat corneal neurons. Brain Res 2006;1085:87–94. Demonstration of the presence of TRPV1 immunoreactive nerve fibers in the cornea.
    1. Canner JP, Linsenmayer TF, Kubilus JK. Developmental regulation of trigeminal TRPA1 by the cornea. Invest Ophthalmol Vis Sci. 2015;56:29–36. doi: 10.1167/iovs.14-15035.
    1. Bautista DM, et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell. 2006;124:1269–1282. doi: 10.1016/j.cell.2006.02.023.
    1. Fajardo O, Meseguer V, Belmonte C, Viana F. TRPA1 channels mediate cold temperature sensing in mammalian vagal sensory neurons: pharmacological and genetic evidence. J Neurosci. 2008;28:7863–7875. doi: 10.1523/JNEUROSCI.1696-08.2008.
    1. Hegarty DM, Hermes SM, Largent-Milnes TM, Aicher SA. Capsaicin-responsive corneal afferents do not contain TRPV1 at their central terminals in trigeminal nucleus caudalis in rats. J Chem Neuroanat. 2014;61–62:1–12. doi: 10.1016/j.jchemneu.2014.06.006.
    1. Stucky CL, Dubin AE, Jeske NA, Malin SA, McKemy DD, Story GM. Roles of transient receptor potential channels in pain. Brain Res Rev. 2009;60:2–23. doi: 10.1016/j.brainresrev.2008.12.018.
    1. Gees M, Owsianik G, Nilius B, Voets T. TRP channels. Compr Physiol. 2012;2:563–608.
    1. Callejo G, Castellanos A, Castany M, Gual A, Luna C, Acosta MC, Gallar J, Giblinn JP, Gasull X. Acid-sensing ion channels detect moderate acidifications to induce ocular pain. Pain. 2015;156:483–495. doi: 10.1097/01.j.pain.0000460335.49525.17.
    1. • McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002;416:52–8. The discovery of TRPM8 channels as cold transducers, made independently of A. Patapoutian’s group (Ref. 51).
    1. • Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A. A TRP channel that senses cold stimuli and menthol. Cell. 2002;108:705–15. The discovery of TRPM8 channels as cold transducers, made independently of D. Julius group (Ref. 50).
    1. • de la Peña E, Malkia A, Cabedo H, Belmonte C, Viana F. The contribution of TRPM8 channels to cold sensing in mammalian neurones. J Physiol. 2005;567:415–26. Seminal papers showing the role of TRPM8 in cold detection.
    1. Latorre R, Brauchi S, Madrid R, Orio P. A cool channel in cold transduction. Physiology. 2011;26:273–285. doi: 10.1152/physiol.00004.2011.
    1. •• Parra A, Gonzalez O, Gallar J, Belmonte C. Tear film hyperosmolality increases nerve impulse activity of cold thermoreceptor endings of the cornea. Pain. 2014;155:1481–91. First experimental demonstration that hyperosmolality in tears excites corneal cold thermoreceptors, proposing a mechanism for the contribution of corneal cold thermoreceptors in dry eye.
    1. Hirata H, Rosenblatt MI. Hyperosmolar tears enhance cooling sensitivity of the corneal nerves in rats: possible neural basis for cold induced dry eye pain. Invest Ophthalmol Vis Sci. 2014;55:5821–5833. doi: 10.1167/iovs.14-14642.
    1. • Reid G, Flonta ML. Cold current in thermoreceptive neurons. Nature. 2001;413:480. The first experimental demonstration of membrane currents activated by cold in primary sensory neurons.
    1. • Viana F, de la Peña E, Belmonte C. Specifity of cold thermotransduction is determined by differential ionic channel expression. Nat Neurosci. 2002;5:254–60. The first demonstration of functionally-specific cold trigeminal ganglion neurons and that several ionic conductances contributed to cold-evoked currents.
    1. Morenilla-Palao C, Luis E, Fernández-Peña C, Quintero E, Weaver JL, Bayliss DA, Viana F. Ion channel profile of TRPM8 cold receptors reveals a role of TASK-3 potassium channels in thermosensation. Cell Rep. 2014;8:1571–1582. doi: 10.1016/j.celrep.2014.08.003.
    1. Madrid R, Donovan-Rodríguez T, Meseguer V, Acosta MC, Belmonte C, Viana F. Contribution of TRPM8 channels to cold transduction in primary sensory neurons and peripheral nerve terminals. J Neurosci. 2006;26:12512–12525. doi: 10.1523/JNEUROSCI.3752-06.2006.
    1. •• Madrid R, de la Peña E, Donovan-Rodriguez T, Belmonte C, Viana F. Variable threshold of cold-sensitive neurons is determined by a balance between TRPM8 and Kv1 potassium channels. J Neurosci. 2009;29:3120–31. The first demonstration of the existence of cold thermoreceptors neurons with different threshold, determined by the variable expression of TRPM8 and Kv1 ion channels.
    1. Belmonte C, Viana F. Molecular and cellular limits to somatosensory specificity. Mol Pain. 2008;4:14. doi: 10.1186/1744-8069-4-14.
    1. Vetter I, Hein A, Sattler S, Hessler S, Touska F, Bressan E, Parra A, Hager U, Leffler A, Boukalova S, Nissen M, Lewis RJ, Belmonte C, Alzheimer C, Huth T, Vlachova V, Reeh P, Zimmermann K. Amplification of cold transduction in native nociceptors by M-channel inhibition. J Neurosci. 2013;33:16627–16641. doi: 10.1523/JNEUROSCI.1473-13.2013.
    1. Petho G, Reeh PW. Sensory and signaling mechanisms of bradykinin, eicosanoids, platelet-activating factor, and nitric oxide in peripheral nociceptors. Physiol Rev. 2012;92:1699–1775. doi: 10.1152/physrev.00048.2010.
    1. Meyer R, Ringkamp R,Campbell JN, Raja SN. Peripheral mechanisms of cutaneous nociception. In: McMahon SB, Koltzenburg M, Tracey I, Turks DC, editors. Wall and Melzack’s textbook of pain. 6th ed., Chapter 1. Philadelphia: Elsevier Saunders; 2013. pp. 3–34.
    1. •• Zhang X, Mak S, Li L, Parra A, Denlinger B, Belmonte C, McNaughton PA. Direct inhibition of the cold-activated TRPM8 ion channel by Gαq. Nat Cell Biol. 2012;14:851–8. The first demonstration that inflammatory mediators inhibit corneal cold thermoreceptors acting directly on TRPM8 channels.
    1. Everill B, Kocsis JD. Reduction in potassium currents in identified cutaneous afferent dorsal root ganglion neurons after axotomy. J Neurophysiol. 1999;82:700–708.
    1. • Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. Sodium channels in normal and pathological pain. Ann Rev Neurosci. 2010;33:325–47. A comprehensive review of the role played by sodium channles in the abnormal excitability of sensory fibers in different pathological conditions, leading to neuropathic pain.
    1. Cruz JS, Silva DF, Ribeiro LA, Araujo IG, Magalhaes N, Medeiros A, Freitas C, Araujo IC, Oliveira FA. Resurgent Na+ current: a new avenue to neuronal excitability control. Life Sci. 2011;89:564–569. doi: 10.1016/j.lfs.2011.05.016.
    1. Liu CY, Lu ZY, Li N, Yu LH, Zhao YF, Ma B. The role of large-conductance, calcium-activated potassium channels in a rat model of trigeminal neuropathic pain. Cephalalgia. 2015;35:16–35. doi: 10.1177/0333102414534083.
    1. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3):S2–S15. doi: 10.1016/j.pain.2010.09.030.
    1. Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature. 1983;306:686–688. doi: 10.1038/306686a0.
    1. Kohno T, Wang H, Amaya F, Brenner GJ, Cheng JK, Ji RR, Woolf CJ. Bradykinin enhances AMPA and NMDA receptor activity in spinal cord dorsal horn neurons by activating multiple kinases to produce pain hypersensitivity. J Neurosci. 2008;28:4533–4540. doi: 10.1523/JNEUROSCI.5349-07.2008.
    1. Bereiter DA, Okamoto K, Tashiro A, Hirata H. Endotoxin-induced uveitis causes long-term changes in trigeminal subnucleus caudalis neurons. J Neurophysiol. 2005;94:3815–3825. doi: 10.1152/jn.00616.2005.
    1. Lee BH, McLaren JW, Erie JC, Hodge DO, Bourne WM. Reinnervation in the cornea after LASIK. Invest Ophthalmol Vis Sci. 2002;43:3660–3664.
    1. •• Gallar J, Acosta MC, Moilanen JAO, Holopainen JM, Belmonte C, Tervo T. Recovery of corneal sensitivity to mechanical and chemical stimulation after laser in situ keratomileusis. J Refract Surg. 2004;20:229–35. First demonstration in humans of the reduction of corneal sensitivity for all sensory modalities after photorefractive surgery.
    1. • Bourcier T, Acosta MC, Borderie V, Borrás F, Gallar J, Bury T, Laroche L, Belmonte C. Decreased corneal sensitivity in dry eye patients. Invest Ophthalmol Vis Sci. 2005;46:2341–5. First demonstration in humans of the reduction of corneal sensitivity for all sensory modalities in dry eye patients.
    1. • Beuerman RW, Schimmelpfennig B. Sensory denervation of the rabbit cornea affects epithelial properties. Exp Neurol. 1980;69:196–201. First description of the morphological changes in corneal sensory nerves following injury and regeneration.
    1. Jordt SE, McKemy DD, Julius D. Lessons from peppers and peppermint: the molecular logic of thermosensation. Curr Opin Neurobiol. 2003;13:487–492. doi: 10.1016/S0959-4388(03)00101-6.
    1. Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, Julius D. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature. 2004;427:260–265. doi: 10.1038/nature02282.
    1. Xing H, Chen M, Ling J, Tan W, Gu JG. TRPM8 mechanism of cold allodynia after chronic nerve injury. J Neurosci. 2007;27:13680–13690. doi: 10.1523/JNEUROSCI.2203-07.2007.
    1. Rivera L, Gallar J, Pozo MA, Belmonte C. Responses of regenerating nerve fibres of the rat saphenous nerve neuroma to mechanical and chemical stimulation. An in vitro study. J Physiol. 2000;527:305–313. doi: 10.1111/j.1469-7793.2000.t01-1-00305.x.
    1. Ma C, Shu Y, Zheng Z, Chen Y, Yao H, Greenquist KW, White FA, LaMotte RH. Similar electrophysiological changes in axotomized and neighboring intact dorsal root ganglion neurons. J Neurophysiol. 2003;9:1588–1602.
    1. Richner M, Ulrichsen M, Elmegaard SL, Dieu R, Pallesen LT, Vaegter CB. Peripheral nerve injury modulates neurotrophin signaling in the peripheral and central nervous system. Mol Neurobiol. 2014;50:945–970. doi: 10.1007/s12035-014-8706-9.
    1. Sessle BJ. Peripheral and central mechanisms of orofacial inflammatory pain. Int Rev Neurobiol. 2011;97:179–206. doi: 10.1016/B978-0-12-385198-7.00007-2.
    1. • Rosenthal P, Borsook D. The corneal pain system. Part I: the missing piece of the dry eye puzzle. Ocul Surf. 2012;10:2–14. A review paper where, based on clinical observations, the relationship between unpleasant ocular surface dryness and neuropathic pain is proposed.
    1. Galor A, Levitt RC, Felix ER, Martin ER, Sarantopoulos CD. Neuropathic ocular pain: an important yet underevaluated feature of dry eye. Eye (Lond) 2014
    1. Zuazo A, Ibañez J, Belmonte C. Sensory nerve responses elicited by experimental ocular hypertension. Exp Eye Res. 1986;43:759–769. doi: 10.1016/S0014-4835(86)80007-0.
    1. Mintenig GM, Sánchez-Vives MV, Martin C, Gual A, Belmonte C. Sensory receptors in the anterior uvea of the cat’s eye. Invest Ophthalmol Vis Sci. 1995;36:1615–1624.
    1. Namavari A, Chaudhary S, Chang JH, Yco L, Sonawane S, Khanolkar V, Yue BY, Sarkar J, Jain S. Cyclosporine immunomodulation retards regeneration of surgically transected corneal nerves. Invest Ophthalmol Vis Sci. 2012;53:732–740. doi: 10.1167/iovs.11-8445.
    1. Gomes PJ, Ousler GW, Welch DL, Smith LM, Coderre J, Abelson MB. Exacerbation of signs and symptoms of allergic conjunctivitis by a controlled adverse environment challenge in subjects with a history of dry eye and ocular allergy. Clin Ophthalmol. 2013;7:157–165. doi: 10.2147/OPTH.S38732.
    1. Acosta MC, Luna CL, Quirce S, Belmonte C, Gallar J. Changes in sensory activity of ocular surface sensory nerves during allergic keratoconjunctivitis. Pain. 2013;154:2353–2362. doi: 10.1016/j.pain.2013.07.012.
    1. Acosta MC, Luna C, Quirce S, Belmonte C, Gallar J. Corneal sensory nerve activity in an experimental model of UV keratitis. Invest Ophthalmol Vis Sci. 2014;55:3403–3412. doi: 10.1167/iovs.13-13774.
    1. Report of the Dry Eye Workshop. Ocul Surf. 2007;5:65–204.
    1. Pflugfelder SC, Stern ME. Mucosal environmental sensors in the pathogenesis of dry eye. Expert Rev Clin Immunol. 2014;10:1137–1140. doi: 10.1586/1744666X.2014.944163.
    1. López-Miguel A, Tesón M, Martín-Montañez V, Enríquez-de-Salamanca A, Stern ME, Calonge M, González-García MJ. Dry eye exacerbation in patients exposed to desiccating stress under controlled environmental conditions. Am J Ophthalmol. 2014;157:788–798. doi: 10.1016/j.ajo.2014.01.001.
    1. Kovács I, Luna C, Quirce S, Mizerska K, Callejo G, Riestra A, Fernández-Sánchez L, Meseguer VM, Cuenca N, Merayo-Lloves J, Gasull X, Acosta MC, Belmonte, C, Gallar J. Abnormal activity of corneal cold thermoreceptors underlies the unpleasant sensations in dry eye disease. 2015 (in press).
    1. •• Kurose M, Meng ID. Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells. J Neurophysiol. 2013;110:495–504. First demonstration of changes in the firing properties of cold thermoreceptor neurons in experimental eye dryness.
    1. Descoeur J, Pereira V, Pizzoccaro A, Francois A, Ling B, Maffre V, Couette B, Busserolles J, Courteix C, Noel J, Lazdunski M, Eschalier A, Authier N, Bourinet E. Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors. EMBO Mol Med. 2011;3:266–278. doi: 10.1002/emmm.201100134.
    1. Belmonte C, Gallar J. Cold thermoreceptors, unexpected players in tear production and ocular dryness sensations. Invest Ophthalmol Vis Sci. 2011;52:3888–3892. doi: 10.1167/iovs.09-5119.
    1. • Lam H, Bleiden L, de Paiva CS, Farley W, Stern ME, Pflugfelder SC. Tear cytokine profiles in dysfunctional tear syndrome. Am J Ophthalmol. 2009;147:198–205. A paper providing data on the contribution of inflammation to dry eye disease.
    1. Stern ME, Schaumburg CS, Pflugfelder SC. Dry eye as a mucosal autoimmune disease. Int Rev Immunol. 2013;32:19–41. doi: 10.3109/08830185.2012.748052.
    1. • Toda I, Asano-Kato N, Komai-Hori Y, Tsubota K. Dry eye after laser in situ keratomileusis. Am J Ophthalmol. 2001;132:1–7. One of the first reports describing the development of dry eye symptoms after LASIK.
    1. Linna T, Tervo T. Real-time confocal microscopic observations on human corneal nerves and wound healing after excimer laser photorefractive keratectomy. Curr Eye Res. 1997;16:640–649. doi: 10.1076/ceyr.16.7.640.5058.
    1. • Gallar J, Acosta MC, Gutiérrez AR, Belmonte C. Impulse activity in corneal sensory nerve fibers after photorefractive keratectomy. Invest Ophthal Vis Sci. 2007;48:4033–7. First recordings of the altered responsiveness of corneal nociceptors following surgical injury.
    1. •• Belmonte C. Eye dryness sensations after refractive surgery. Impaired tear secretion or ‘phantom’ cornea? J Refract Surg. 2007;23:598–602. First proposal that dryness sensations experienced by dry eye patients are due to neuropathic ocular pain and not ocular surface dryness.
    1. •• Stapleton F, Marfurt C, Golebiowski B, Rosenblatt M, Bereiter D, Begley C, Dartt D, Gallar J, Belmonte C, Hamrah P, Willcox M. The TFOS international workshop on contact lens discomfort: report of the subcommittee on neurobiology. Invest Ophthalmol Vis Sci. 2013;54:TFOS71–97. A complete and updated revision of ocular surface pain.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться