Effect of COX-1 and COX-2 Inhibition on Induction and Maintenance of Carrageenan-Evoked Thermal Hyperalgesia in Rats1
- Departments of 1Anesthesiology (T.L.Y.) and 2Pharmacology (D.M.D., T.L.Y.), University of California, San Diego, California
Abstract
Intrathecal administration of nonsteroidal anti-inflammatory drugs in the rat blocks the thermal hyperalgesia induced by tissue injury, which suggests a role for spinal cyclooxygenase (COX) products in this facilitated state. Two isozymes of the COX enzyme have been reported, COX-1 and COX-2, but the agents thus far examined are not isozyme selective. We examined the effects of intrathecally (i.t.) or systemically (i.p.) administered S(+)-ibuprofen (a nonselective COX inhibitor) or 1-[(4-methysulfonyl)phenyl]-3-tri-fluoromethyl-5-(4-fluorophenyl) pyrazole (SC58125; a COX-2 selective inhibitor) on carrageenan-induced thermal hyperalgesia (reduced hindpaw-withdrawal latency). The following observations were made: 1) Thermal hyperalgesia otherwise observed during the first 170 min was blocked in a dose-dependent manner by S(+)-ibuprofen or SC58125 administered i.t. or i.p. before carrageenan treatment. 2) Intraperitoneal, but not i.t., administration of either inhibitor after the establishment of hyperalgesia (170 min after carrageenan injection) reversed thermal hyperalgesia in a dose-dependent manner. Thus, the initial component of thermal hyperalgesia after tissue injury was blocked by systemic or spinal administration of both COX inhibitors, whereas established hyperalgesia was reversed only by systemic inhibitors. This study demonstrates that at least spinal COX-2, if not both COX-1 and COX-2, are necessary for the initiation of thermal hyperalgesia, whereas nonspinal sources of prostanoids (synthesized by COX-2 and perhaps also COX-1) are important for the maintenance of thermal hyperalgesia associated with tissue injury and inflammation.
Footnotes
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Send reprint requests to: Tony L. Yaksh, Ph.D., University of California, San Diego, Department of Anesthesiology, 9500 Gilman Drive, Mail Code 0818, La Jolla, CA 92093-0818.
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↵1 Research supported in part by National Institutes of Health grant NIDA02110 (to T.L.Y.) and Pre-Doctoral National Research Service Award NIDA05726 (to D.M.D.).
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2 Current address: Searle Research and Development, St. Louis, MO 63198.
- Abbreviations:
- COX
- cyclooxygenase
- COX-1
- cyclooxygenase-1
- COX-2
- cyclooxygenase-2
- NMDA
- N-methyl-d-aspartate
- PG
- prostaglandin
- PGE2
- prostaglandin E2
- PGI2
- prostaglandin I2 (prostacyclin)
- i.t.
- intrathecal
- i.p.
- intraperitoneal
- AUC
- area under the curve
- SC58125
- 1-[(4-methysulfonyl)phenyl]-3-tri-fluoromethyl-5-(4-fluorophenyl)pyrazole
- NSAID
- nonsteroidal anti-inflammatory drug
- PWL
- paw-withdrawal latency
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- Received November 10, 1997.
- Accepted February 26, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
