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Vol. 283, Issue 3, 1069-1075, 1997
Searle Research and Development, Monsanto, St. Louis, Missouri
PGs derived from cyclooxygenase-2 (COX-2), in particular
PGE2, play important roles in the initiation of
inflammation and pain. In the present study, we evaluated the role of
COX-2-derived PGE2 in an animal model of established
hyperalgesia. Inflammation and hyperalgesia were first induced by
injection of carrageenan into rat footpads. Then we investigated the
effects of subsequent therapeutic treatment with a selective COX
inhibitor, with a nonsteroidal anti-inflammatory drug and with
anti-PGE2 antibody. Test compounds were administered 1 to 3 hr after carrageenan challenge, and inhibition of pain (hyperalgesia,
measured by withdrawal from a thermal stimulus), and changes in paw
edema and PG levels were evaluated. The i.v. administration of a
nonselective COX inhibitor, ketorolac, caused a rapid reduction in
hyperalgesia in the inflamed footpad, returning it to near-normal
values within 1 hr. Normal (control) paw response times were not
affected. Therapeutic administration of ketorolac prevented most
further swelling caused by carrageenan but did not reverse edema
already present at the time of dosing. Administered p.o., a selective
COX-2 inhibitor (SC-58635) was as efficacious as ketorolac in reducing
inflammatory hyperalgesia. Footpad PG levels returned to base line or
below within 5 min of dosing with ketorolac, which suggests rapid
turnover of PG in the inflamed tissue. Therapeutic treatment with a
monoclonal anti-PGE2 antibody also fully reversed the
hyperalgesia response. These studies suggest that continuous production
of PGE2 by the COX-2 enzyme is a critical element in
sustaining the hyperalgesic response at sites of tissue inflammation.
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