PHARMACOLOGICAL ANALYSIS OF CYCLOOXYGENASE-1 IN INFLAMMATION

The enzymes cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) ca talyze the conversion of arachidonic acid to prostaglandin (PG) H-2, t he precursor of PGs and thromboxane. These lipid mediators play import ant roles in inflammation and pain and in normal physiological functio ns. While there are abundant data indicating that the inducible isofor m, COX-2, is important in inflammation and pain, the constitutively ex pressed isoform, COX-1, has also been suggested to play a role in infl ammatory processes. To address the latter question pharmacologically, we used a highly selective COX-1 inhibitor, SC-560 (COX-1 IC50 = 0.009 mu M; COX-2 IC50 = 6.3 mu M). SC-560 inhibited COX-1-derived platelet thromboxane B-2, gastric PGE(2), and dermal PGE(2) production, indica ting that it was orally active, but did not inhibit COX-2-derived PGs in the lipopolysaccharide-induced rat air pouch. Therapeutic or prophy lactic administration of SC-560 in the rat carrageenan footpad model d id not affect acute inflammation or hyperalgesia at doses that markedl y inhibited in vivo COX-1 activity. By contrast, celecoxib, a selectiv e COX-2 inhibitor, was anti-inflammatory and analgesic in this model. Paradoxically, both SC-560 and celecoxib reduced paw PGs to equivalent levels. Increased levels of PGs were found in the cerebrospinal fluid after carrageenan injection and were markedly reduced by celecoxib, b ut were not affected by SC-560, These results suggest that, in additio n to the role of peripherally produced PGs, there is a critical, centr ally mediated neurological component to inflammatory pain that is medi ated at least in part by COX-2.