The pruritogenic and inflammatory effects of prostanoids in the conjunctiva.
The therapeutic utility of cyclooxygenase (CO) inhibitors, such as ketorolac, in reducing the inflammatory events associated with allergic conjunctivitis is not unexpected since prostanoids (PG) elicit conjunctival redness (PGD2, PGE2, PGF2 alpha), edema (PGD2, TxA2), eosinophil infiltration (PGD2, PGJ2) and mucous cell discharge (PGD2, PGJ2, TxA2). Recently, topically administered ketorolac has also been reported to alleviate the itching associated with allergic conjunctivitis. This was viewed as intriguing since CO inhibitors are not regarded as useful for treating itching dermatoses and PGs do not elicit itching when applied to the skin. In order to investigate the antipruritic activity of ketorolac, we developed a model for reproducibly measuring ocular surface itch responses. The model involves itch-scratch responses to pruritogens applied locally to the ocular surface. Painful and foreign body stimuli do not produce an itch-scratch response. Unlike reported skin studies, PGE2 was a potent itch-producing substances in the conjunctiva. PGD2 was weakly pruritogenic but PGF2 alpha and the TxA2-mimetic U-46619 were inactive. The PG precursor arachidonic acid was also a potent pruritogen and its effects were inhibited by ketorolac pretreatment. Ketorolac also dose-dependently inhibited the itching associated with experimental allergic conjunctivitis. It appears that PGs are potent itch-producing substances in the conjunctiva and the anti-itch efficacy of ketorolac in allergic conjunctivitis appears to involve inhibition of conjunctival PG biosynthesis from arachidonic acid.
Woodward
D F
DF
Department of Biosciences, Allergan, Inc., Irvine, California, USA.
Nieves
A L
AL
Hawley
S B
SB
Joseph
R
R
Merlino
G F
GF
Spada
C S
CS
D000818:Animals; D002199:Capillary Permeability; D003228:Conjunctiva / Q000098:blood supply / Q000187:drug effects*; D003233:Conjunctivitis, Allergic / Q000209:etiology / Q000517:prevention & control*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007476:Ionophores; D020910:Ketorolac; D008297:Male; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology* / Q000627:therapeutic use; D011537:Pruritus / Q000209:etiology / Q000517:prevention & control*; D014046:Tolmetin / Q000031:analogs & derivatives / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D007476:Ionophores; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D014046:Tolmetin; D020910:Ketorolac