Inhibition of cyclooxygenase-2 rapidly reverses inflammatory hyperalgesia and prostaglandin E2 production.
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.
Zhang
Y
Y
Searle Research and Development, Monsanto, St. Louis, Missouri, USA.
Shaffer
A
A
Portanova
J
J
Seibert
K
K
Isakson
P C
PC
D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis*; D006930:Hyperalgesia / Q000517:prevention & control*; D007249:Inflammation / Q000503:physiopathology*; D020910:Ketorolac; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014046:Tolmetin / Q000031:analogs & derivatives / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D014046:Tolmetin; D015232:Dinoprostone; D020910:Ketorolac