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OtherANALGESIA AND DRUGS OF ABUSE

Effect of COX-1 and COX-2 Inhibition on Induction and Maintenance of Carrageenan-Evoked Thermal Hyperalgesia in Rats

David M. Dirig, Peter C. Isakson and Tony L. Yaksh
Journal of Pharmacology and Experimental Therapeutics June 1998, 285 (3) 1031-1038;
David M. Dirig
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Peter C. Isakson
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Tony L. Yaksh
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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

  • 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.

  • ↵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.).

  • 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
    • Received November 10, 1997.
    • Accepted February 26, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 3
1 Jun 1998
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OtherANALGESIA AND DRUGS OF ABUSE

Effect of COX-1 and COX-2 Inhibition on Induction and Maintenance of Carrageenan-Evoked Thermal Hyperalgesia in Rats

David M. Dirig, Peter C. Isakson and Tony L. Yaksh
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1031-1038;

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OtherANALGESIA AND DRUGS OF ABUSE

Effect of COX-1 and COX-2 Inhibition on Induction and Maintenance of Carrageenan-Evoked Thermal Hyperalgesia in Rats

David M. Dirig, Peter C. Isakson and Tony L. Yaksh
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1031-1038;
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