Advertisement

Topical Tetrodotoxin Attenuates Photophobia Induced by Corneal Injury in the Rat

  • Paul G. Green
    Affiliations
    Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, California

    Department of Preventative & Restorative Dental Sciences, University of California at San Francisco, San Francisco, California

    Division of Neuroscience, University of California at San Francisco, San Francisco, California
    Search for articles by this author
  • Pedro Alvarez
    Affiliations
    Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, California

    Division of Neuroscience, University of California at San Francisco, San Francisco, California
    Search for articles by this author
  • Jon D. Levine
    Correspondence
    Address reprint requests to Jon D. Levine, MD, PhD, Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA 94143-0440.
    Affiliations
    Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, California

    Division of Neuroscience, University of California at San Francisco, San Francisco, California

    Department of Dental Science and Medicine, University of California at San Francisco, San Francisco, California
    Search for articles by this author

      Highlights

      • Corneal injury produced an increased sensitivity to light (photophobia).
      • Tetrodotoxin and lidocaine had no effect on light-aversive behavior in normal control rats.
      • Tetrodotoxin and lidocaine both eliminated photophobia in rats with corneal injury.
      • Because of lidocaine corneal toxicity, topical tetrodotoxin may be a safer therapeutic option.

      Abstract

      Corneal injury can produce photophobia, an aversive sensitivity to light. Using topical application of lidocaine, a local anesthetic, and tetrodotoxin (TTX), a selective voltage-sensitive sodium channel blocker, we assessed whether enhanced aversiveness to light induced by corneal injury in rats was caused by enhanced activity in corneal afferents. Eye closure induced by 30 seconds of exposure to bright light (460–485 nm) was increased 24 hours after corneal injury induced by de-epithelialization. Although the topical application of lidocaine did not affect the baseline eye closure response to bright light in control rats, it eliminated the enhancement of the response to the light stimulus after corneal injury (photophobia). Similarly, topical application of TTX had no effect on the eye closure response to bright light in rats with intact corneas, but it markedly attenuated photophobia in rats with corneal injury. Given the well-established corneal toxicity of local anesthetics, we suggest TTX as a therapeutic option to treat photophobia and possibly other symptoms that occur in clinical diseases that involve corneal nociceptor sensitization.

      Perspective

      We show that lidocaine and TTX attenuate photophobia induced by corneal injury. Although corneal toxicity limits use of local anesthetics, TTX may be a safer therapeutic option to reduce the symptom of photophobia associated with corneal injury.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Belmonte C.
        • Acosta M.C.
        • Gallar J.
        Neural basis of sensation in intact and injured corneas.
        Exp Eye Res. 2004; 78: 513-525
        • Berson D.M.
        Phototransduction in ganglion-cell photoreceptors.
        Pflugers Arch. 2007; 454: 849-855
        • Bi R.Y.
        • Kou X.X.
        • Meng Z.
        • Wang X.D.
        • Ding Y.
        • Gan Y.H.
        Involvement of trigeminal ganglionic Nav 1.7 in hyperalgesia of inflamed temporomandibular joint is dependent on ERK1/2 phosphorylation of glial cells in rats.
        Eur J Pain. 2013; 17: 983-994
        • Binder P.S.
        Optical problems following refractive surgery.
        Ophthalmology. 1986; 93: 739-745
        • Bisla K.
        • Tanelian D.L.
        Concentration-dependent effects of lidocaine on corneal epithelial wound healing.
        Invest Ophthalmol Vis Sci. 1992; 33: 3029-3033
        • Çavuş U.Y.
        • Avci S.
        • Sönmez E.
        • Doğan M.S.
        • Gürer B.
        Isolated photophobia as a presenting symptom of spontaneous subarachnoid hemorrhage.
        Clin Neurol Neurosurg. 2014; 122: 138-139
        • Chan K.Y.
        • Jones R.R.
        • Bark D.H.
        • Swift J.
        • Parker Jr., J.A.
        • Haschke R.H.
        Release of neuronotrophic factor from rabbit corneal epithelium during wound healing and nerve regeneration.
        Exp Eye Res. 1987; 45: 633-646
        • Chao C.
        • Golebiowski B.
        • Stapleton F.
        The role of corneal innervation in LASIK-induced neuropathic dry eye.
        Ocul Surf. 2014; 12: 32-45
        • Committee for the Update of the Guide for the Care and Use of Laboratory Animals
        Guide for the Care and Use of Laboratory Animals.
        in: 8th ed. The National Academies Press, Washington, DC2011
        • Dib-Hajj S.D.
        • Yang Y.
        • Black J.A.
        • Waxman S.G.
        The Na(V)1.7 sodium channel: from molecule to man.
        Nat Rev Neurosci. 2013; 14: 49-62
        • Digre K.B.
        • Brennan K.C.
        Shedding light on photophobia.
        J Neuroophthalmol. 2012; 32: 68-81
        • Erdem E.
        • Undar I.H.
        • Esen E.
        • Yar K.
        • Yagmur M.
        • Ersoz R.
        Topical anesthetic eye drops abuse: are we aware of the danger?.
        Cutan Ocul Toxicol. 2013; 32: 189-193
        • Gallar J.
        • Acosta M.C.
        • Gutierrez A.R.
        • Belmonte C.
        Impulse activity in corneal sensory nerve fibers after photorefractive keratectomy.
        Invest Ophthalmol Vis Sci. 2007; 48: 4033-4037
        • Graham J.S.
        • Schoneboom B.A.
        Historical perspective on effects and treatment of sulfur mustard injuries.
        Chem Biol Interact. 2013; 206: 512-522
        • Katagiri A.
        • Thompson R.
        • Rahman M.
        • Okamoto K.
        • Bereiter D.A.
        Evidence for TRPA1 involvement in central neural mechanisms in a rat model of dry eye.
        Neuroscience. 2015; 290: 204-213
        • Kayser V.
        • Viguier F.
        • Ioannidi M.
        • Bernard J.F.
        • Latremoliere A.
        • Michot B.
        • Vela J.M.
        • Buschmann H.
        • Hamon M.
        • Bourgoin S.
        Differential anti-neuropathic pain effects of tetrodotoxin in sciatic nerve- versus infraorbital nerve-ligated rats–behavioral, pharmacological and immunohistochemical investigations.
        Neuropharmacology. 2010; 58: 474-487
        • Klugbauer N.
        • Lacinova L.
        • Flockerzi V.
        • Hofmann F.
        Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells.
        EMBO J. 1995; 14: 1084-1090
        • Lampert A.
        • O’Reilly A.O.
        • Reeh P.
        • Leffler A.
        Sodium channelopathies and pain.
        Pflugers Arch. 2010; 460: 249-263
        • Lyu Y.S.
        • Park S.K.
        • Chung K.
        • Chung J.M.
        Low dose of tetrodotoxin reduces neuropathic pain behaviors in an animal model.
        Brain Res. 2000; 871: 98-103
        • Maleki N.
        • Becerra L.
        • Upadhyay J.
        • Burstein R.
        • Borsook D.
        Direct optic nerve pulvinar connections defined by diffusion MR tractography in humans: implications for photophobia.
        Hum Brain Mapp. 2012; 33: 75-88
        • McGee H.T.
        • Fraunfelder F.W.
        Toxicities of topical ophthalmic anesthetics.
        Expert Opin Drug Saf. 2007; 6: 637-640
        • Miller S.
        • Mateen F.J.
        • Aksamit A.J.
        Herpes simplex virus 2 meningitis: a retrospective cohort study.
        J Neurovirol. 2013; 19: 166-171
        • Mukai M.
        • Sakuma Y.
        • Suzuki M.
        • Orita S.
        • Yamauchi K.
        • Inoue G.
        • Aoki Y.
        • Ishikawa T.
        • Miyagi M.
        • Kamoda H.
        • Kubota G.
        • Oikawa Y.
        • Inage K.
        • Sainoh T.
        • Sato J.
        • Nakamura J.
        • Takaso M.
        • Toyone T.
        • Takahashi K.
        • Ohtori S.
        Evaluation of behavior and expression of NaV1.7 in dorsal root ganglia after sciatic nerve compression and application of nucleus pulposus in rats.
        Eur Spine J. 2014; 23: 463-468
        • Nieto F.R.
        • Cobos E.J.
        • Tejada M.A.
        • Sanchez-Fernandez C.
        • Gonzalez-Cano R.
        • Cendan C.M.
        Tetrodotoxin (TTX) as a therapeutic agent for pain.
        Mar Drugs. 2012; 10: 281-305
        • Noseda R.
        • Kainz V.
        • Jakubowski M.
        • Gooley J.J.
        • Saper C.B.
        • Digre K.
        • Burstein R.
        A neural mechanism for exacerbation of headache by light.
        Nat Neurosci. 2010; 13: 239-245
        • Okamoto K.
        • Tashiro A.
        • Chang Z.
        • Bereiter D.A.
        Bright light activates a trigeminal nociceptive pathway.
        Pain. 2010; 149: 235-242
        • Okamoto K.
        • Tashiro A.
        • Thompson R.
        • Nishida Y.
        • Bereiter D.A.
        Trigeminal interpolaris/caudalis transition neurons mediate reflex lacrimation evoked by bright light in the rat.
        Eur J Neurosci. 2012; 36: 3492-3499
        • Panneton W.M.
        • 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
        • Patel M.
        • Fraunfelder F.W.
        Toxicity of topical ophthalmic anesthetics.
        Expert Opin Drug Metab Toxicol. 2013; 9: 983-988
        • Pearlman E.
        • Sun Y.
        • Roy S.
        • Karmakar M.
        • Hise A.G.
        • Szczotka-Flynn L.
        • Ghannoum M.
        • Chinnery H.R.
        • McMenamin P.G.
        • Rietsch A.
        Host defense at the ocular surface.
        Int Rev Immunol. 2013; 32: 4-18
        • Perez-Castro R.
        • Patel S.
        • Garavito-Aguilar Z.V.
        • Rosenberg A.
        • Recio-Pinto E.
        • Zhang J.
        • Blanck T.J.
        • Xu F.
        Cytotoxicity of local anesthetics in human neuronal cells.
        Anesth Analg. 2009; 108: 997-1007
        • Plainis S.
        • Murray I.J.
        • Carden D.
        The dazzle reflex: electrophysiological signals from ocular muscles reveal strong binocular summation effects.
        Ophthalmic Physiol Opt. 2006; 26: 318-325
        • Rittichier K.K.
        • Roback M.G.
        • Bassett K.E.
        Are signs and symptoms associated with persistent corneal abrasions in children?.
        Arch Pediatr Adolesc Med. 2000; 154: 370-374
        • Rosenthal P.
        • Borsook D.
        The corneal pain system. Part I: the missing piece of the dry eye puzzle.
        Ocul Surf. 2012; 10: 2-14
        • Sainz de la Maza M.
        • Molina N.
        • Gonzalez-Gonzalez L.A.
        • Doctor P.P.
        • Tauber J.
        • Foster C.S.
        Clinical characteristics of a large cohort of patients with scleritis and episcleritis.
        Ophthalmology. 2012; 119: 43-50
        • Schwartz D.M.
        • Duncan K.G.
        • Fields H.L.
        • Jones M.R.
        Tetrodotoxin: anesthetic activity in the de-epithelialized cornea.
        Graefes Arch Clin Exp Ophthalmol. 1998; 236: 790-794
        • Schwartz D.M.
        • Fields H.L.
        • Duncan K.G.
        • Duncan J.L.
        • Jones M.R.
        Experimental study of tetrodotoxin, a long-acting topical anesthetic.
        Am J Ophthalmol. 1998; 125: 481-487
        • Selmi C.
        Diagnosis and classification of autoimmune uveitis.
        Autoimmun Rev. 2014; 13: 591-594
        • Sheedy J.E.
        • Truong S.D.
        • Hayes J.R.
        What are the visual benefits of eyelid squinting?.
        Optom Vis Sci. 2003; 80: 740-744
        • Shields S.D.
        • Cheng X.
        • Uceyler N.
        • Sommer C.
        • Dib-Hajj S.D.
        • Waxman S.G.
        Sodium channel Na(v)1.7 is essential for lowering heat pain threshold after burn injury.
        J Neurosci. 2012; 32: 10819-10832
        • Shtein R.M.
        Post-LASIK dry eye.
        Expert Rev Ophthalmol. 2011; 6: 575-582
        • Wang X.L.
        • Elgjo K.
        • Haaskjold E.
        Regeneration of rat corneal epithelium is delayed by the inhibitory epidermal pentapeptide (EPP).
        Acta Ophthalmol Scand. 1996; 74: 361-363
        • Xie W.
        • Strong J.A.
        • Meij J.T.
        • Zhang J.M.
        • Yu L.
        Neuropathic pain: early spontaneous afferent activity is the trigger.
        Pain. 2005; 116: 243-256
        • Yu H.Z.
        • Li Y.H.
        • Wang R.X.
        • Zhou X.
        • Yu M.M.
        • Ge Y.
        • Zhao J.
        • Fan T.J.
        Cytotoxicity of lidocaine to human corneal endothelial cells in vitro.
        Basic Clin Pharmacol Toxicol. 2014; 114: 352-359