Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat.
Subcutaneous injection of formalin into the dorsal surface of the hindpaw evoked a two-phased flinching (phase 1:0-9 min; phase 2: 10-60 min) of the injected paw. Intrathecal administration of the nonsteroidal anti-inflammatory drugs (NSAID) produced minimal effects upon phase 1, but showed a significant, though submaximal, dose-dependent suppression of the phase 2 response. Ordering of i.t. potency was (ID50 in nmol): indomethacin (1.9) > or = flurbiprofen (2.1) > ketorolac (5.2) > or = zomepirac (5.9) > S(+)ibuprofen (16) > or = ibuprofen(racemic) (19) > acetylsalicylic acid (27) > acetaminophen (250) > R(-)ibuprofen (> 270) = 0. Intraperitoneal administration also produced a dose-dependent inhibition of phase 2, but only at doses which were 100 to 1000 times higher than those required to produce similar effects after i.t. injection. Intrathecal and i.p. dose-response curves showed similar distinct plateaus of maximum achievable inhibition (intrinsic activity) of the phase 2 behavior, ranging from 20 to 50% of the control response. Varying the time of drug injection reveals that injection 9 min after formalin yielded effects the same as those observed when the agent was given 2 min before formalin. Pretreatment at longer intervals indicated that the duration of the antinociceptive effect was between 3 to 6 hr after the i.t. injection. The i.t. injection of the highest doses of the several NSAID were without significant effect upon the 52.5 degrees C hot plate test. These studies indicate that NSAID have a powerful effect upon spinal nociceptive processing evoked by the s.c. injection of formalin.
Malmberg
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AB
Department of Anesthesiology, University of California, San Diego, La Jolla.
Yaksh
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TL
D000698:Analgesia; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde / Q000037:antagonists & inhibitors* / Q000633:toxicity; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005557:Formaldehyde