Prolonged analgesic response of cornea to topical resiniferatoxin, a potent TRPV1 agonist.
Analgesics currently available for the treatment of pain following ophthalmic surgery or injury are limited by transient effectiveness and undesirable or adverse side effects. The cornea is primarily innervated by small-diameter C-fiber sensory neurons expressing TRPV1 (transient receptor potential channel, subfamily V, member 1), a sodium/calcium cation channel expressed abundantly by nociceptive neurons and consequently a target for pain control. Resiniferatoxin (RTX), a potent TRPV1 agonist, produces transient analgesia when injected peripherally by inactivating TRPV1-expressing nerve terminals through excessive calcium influx. The aim of the present study was to evaluate topical RTX as a corneal analgesic. In rat cornea, a single application of RTX dose dependently eliminated or reduced the capsaicin eye wipe response for 3-5 days, with normal nociceptive responses returning by 5-7 days. RTX alone produced a brief but intense noxious response, similar to capsaicin, necessitating pretreatment of the cornea with a local anesthetic. Topical lidocaine, applied prior to RTX, blocks acute nociceptive responses to RTX without impairing the subsequent analgesic effect. Importantly, RTX analgesia (a) did not impair epithelial wound healing, (b) left the blink reflex intact and (c) occurred without detectable histological damage to the cornea. Immunohistochemistry showed that loss of CGRP immunoreactivity, a surrogate marker for TRPV1-expressing fibers, extended at least to the corneal-scleral boundary and displayed a progressive return, coincident with the return of capsaicin sensitivity. These data suggest that RTX may be a safe and effective treatment for post-operative or post-injury ophthalmic pain.
Bates
Brian D
BD
Neurobiology and Pain Therapeutics Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20982, USA Immunopathology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20982, USA Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20982, USA Division of Anesthesia and Surgical Services, Clinical Center, National Institutes of Health, Bethesda, MD 20982, USA.
Mitchell
Kendall
K
Keller
Jason M
JM
Chan
Chi-Chao
CC
Swaim
William D
WD
Yaskovich
Ruth
R
Mannes
Andrew J
AJ
Iadarola
Michael J
MJ
D000287:Administration, Topical; D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003315:Cornea / Q000187:drug effects* / Q000294:innervation* / Q000503:physiopathology; D004195:Disease Models, Animal; D004224:Diterpenes / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists* / Q000378:metabolism; D016896:Treatment Outcome
D000700:Analgesics; D004224:Diterpenes; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C024353:resiniferatoxin
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