The
enzymes cyclooxygenase-1 and
cyclooxygenase-2 (COX-1 and COX-2) catalyze the conversion of
arachidonic acid to
prostaglandin (PG) H2, the precursor of PGs and
thromboxane. These
lipid mediators play important roles in
inflammation and
pain and in normal physiological functions. While there are abundant data indicating that the inducible
isoform, COX-2, is important in
inflammation and
pain, the constitutively expressed
isoform, COX-1, has also been suggested to play a role in inflammatory processes. To address the latter question pharmacologically, we used a highly selective COX-1 inhibitor,
SC-560 (COX-1 IC50 = 0.009 microM; COX-2 IC50 = 6.3 microM).
SC-560 inhibited COX-1-derived platelet
thromboxane B2, gastric
PGE2, and dermal
PGE2 production, indicating that it was orally active, but did not inhibit COX-2-derived PGs in the
lipopolysaccharide-induced rat air pouch. Therapeutic or prophylactic administration of
SC-560 in the rat
carrageenan footpad model did not affect acute
inflammation or
hyperalgesia at doses that markedly inhibited in vivo COX-1 activity. By contrast,
celecoxib, a selective
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, but were not affected by
SC-560. These results suggest that, in addition to the role of peripherally produced PGs, there is a critical, centrally mediated neurological component to inflammatory
pain that is mediated at least in part by COX-2.