Comparative effects of the nonsteroidal anti-inflammatory drug nepafenac on corneal sensory nerve fibers responding to chemical irritation.
OBJECTIVE
To compare the corneal analgesic efficacy of the nonsteroidal anti-inflammatory drugs (NSAIDs) nepafenac, diclofenac, and ketorolac, and to evaluate the possibility that their inhibitory effects on corneal polymodal nociceptor fiber activity are partly mediated by a decrease in sodium currents.


METHODS
Corneal sensory afferent units were recorded in the anesthetized cat. The response of thin myelinated polymodal nociceptor fibers to mechanical and acidic stimulation (98.5% CO(2)) was recorded before and at various times after topical application of the vehicle or of nepafenac 0.1% (Nevanac; Alcon Laboratories, Ltd., Fort Worth, TX), diclofenac 0.1% (Voltaren; Novartis, Basel, Switzerland), and ketorolac 0.4% (Acular LS; Allergan, Irvine, CA). Voltage-clamp recordings were performed in cultured trigeminal ganglion neurons.


RESULTS
Nepafenac, diclofenac, and ketorolac reduced the mean frequency of the impulse response evoked by repeated CO(2) stimuli in polymodal nociceptor fibers. The progressive increase in ongoing activity, observed in vehicle-treated eyes after repeated acidic stimulation was also prevented. Nepafenac exhibited a more rapid and a slightly more pronounced effect on spontaneous and CO(2)-evoked activity than did diclofenac and ketorolac and did not affect the responsiveness of corneal mechanonociceptor or cold receptor fibers. In cultured mice trigeminal ganglion neurons, diclofenac significantly suppressed sodium currents, whereas nepafenac or its metabolite, amfenac, exhibited only minimal inhibitory effects.


CONCLUSIONS
The inhibition of polymodal nociceptor activity by nepafenac, a weak inhibitor of cyclooxygenase, is most likely due to its greater lipophilicity compared with diclofenac and ketorolac, leading to a rapid saturation of the corneal epithelium where nociceptor terminals are located. In contrast to diclofenac, nepafenac does not exhibit local anesthetic effects.
Acosta
M Carmen
MC
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain. mcarmen.acosta@umh.es
Luna
Carolina
C
Graff
Gustav
G
Meseguer
Victor M
VM
Viana
Felix
F
Gallar
Juana
J
Belmonte
Carlos
C
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D044482:Benzeneacetamides / Q000494:pharmacology*; D002245:Carbon Dioxide; D002415:Cats; D002478:Cells, Cultured; D003315:Cornea / Q000294:innervation*; D004008:Diclofenac / Q000494:pharmacology; D005260:Female; D020910:Ketorolac / Q000494:pharmacology; D008297:Male; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010648:Phenylacetates / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000187:drug effects* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D044482:Benzeneacetamides; D010648:Phenylacetates; D015222:Sodium Channels; C414203:nepafenac; D002245:Carbon Dioxide; D004008:Diclofenac; D020910:Ketorolac