CHARACTERIZATION OF RECEPTOR SUBTYPES INVOLVED IN PROSTANOID-INDUCED CONJUNCTIVAL PRURITUS AND THEIR ROLE IN MEDIATING ALLERGIC CONJUNCTIVAL ITCHING

Topically administered ketorolac (Acular), a cyclooxygenase inhibitor, has recently been reported as clinically beneficial for treating alle rgic conjunctivitis. The ability of ketorolac to relieve the itching a ssociated with allergic conjunctivitis is intriguing because cyclooxyg enase inhibitors are not regarded as useful in treating allergic derma toses and prostaglandins (PG) do not elicit an itch response in human skin. To gain further insight into the mechanisms involved in the anti pruritic activity of ketorolac, we used a method of reproducibly asses sing ocular surface itch responses in the guinea pig. The measurement of conjunctival pruritus involved a recently developed behavioral mode l whereby hind limb scratching episodes directed toward the afflicted area were quantified. Itch-scratch episodes have previously been delin eated from foreign body and pain sensations, which do not evoke such a behavioral response. Ketorolac significantly inhibited the itching as sociated with experimental allergic conjunctivitis. The basis of this antipruritic activity may be ascribed to preventing the biosynthesis o f itch-producing PGs because ketorolac inhibited arachidonic acid-indu ced pruritus. In contrast to skin studies, PGE(2) and PGI(2) were foun d to be potent pruritogens at the guinea pig ocular surface. PGD(2) wa s a weak pruritogen, and PGF(2 alpha) and the thromboxanemimetic U-466 19 produced no meaningful response. Further studies involving selectiv e agonists and antagonists suggested that EP(1) receptors, IP receptor s and PGD(2)-sensitive receptors may mediate prostanoid-induced conjun ctival itching. No evidence for the involvement of other prostanoid re ceptor subtypes was obtained. Although the EP(1) receptor antagonist A H 6809 and the DP receptor antagonist BW A868C inhibited PGE(2)- and P GD(2)-induced itching, respectively, neither antagonist alone signific antly affected the itching associated with experimental allergic conju nctivitis. A combination of AH 6809 and BW A868C, however, did exhibit antipruritic activity. It appears that for effective relief of itchin g in allergic conjunctivitis, it is not sufficient to block the effect s of a single pruritogenic PG. It is preferable to reduce the particip ation of all pruritogenic PGs by either using combined receptor antago nists or by using a cyclooxygenase inhibitor such as ketorolac to bloc k their biosynthesis.