QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.069484v1 311/1/356    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Koetzner, L. Articles by Yaksh, T. L. Search for Related Content PubMed PubMed Citation Articles by Koetzner, L. Articles by Yaksh, T. L.

NEUROPHARMACOLOGY

Intrathecal Protease-Activated Receptor Stimulation Produces Thermal Hyperalgesia through Spinal Cyclooxygenase Activity

Anesthesiology Research Laboratory 0818 (L.K., J.A.G., T.L.Y); and Department of Pharmacology, University of California, San Diego, La Jolla, California (T.L.Y.)

Activation of protease-activated receptors (PARs) in non-neural tissue results in prostaglandin production. Because PARs are found in the spinal cord and increased prostaglandin release in the spinal cord causes thermal hyperalgesia, we hypothesized that activation of these spinal PARs would stimulate prostaglandin production and cause a cyclooxygenase-dependent thermal hyperalgesia. PARs were activated using either thrombin or peptide agonists derived from the four PAR subtypes, delivered to the lumbar spinal cord. Dialysis experiments were conducted in conscious, unrestrained rats using loop microdialysis probes placed in the lumbar intrathecal space. Intrathecal thrombin stimulated release of prostaglandin E (PGE)₂ but not aspartate or glutamate. Intrathecal delivery of the PAR 1-derived peptide SFLLRN-NH₂ and the PAR 2-derived peptide SLIGRL both stimulated PGE₂ release; PAR 3-derived TFRGAP and PAR 4-derived GYPGQV were inactive. Intrathecal thrombin had no effect upon formalin-induced flinching or tactile sensitivity but resulted in a thermal hyperalgesia. Intrathecal SFLLRN-NH₂ and SLIGRL both produced thermal hyperalgesia. Consistent with their effects on spinal PGE₂, hyperalgesia from these peptides was blocked by pretreatment with the cyclooxygenase inhibitor ibuprofen. SLIGRL-induced hyperalgesia was also blocked by the selective inhibitors SC 58,560 [5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole; cyclooxygenase (COX) 1] and SC 58,125 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; COX 2]. These data indicate that activation of spinal PAR 2 and possibly PAR 1 results in the stimulation of the spinal cyclooxygenase cascade and a prostaglandin-dependent thermal hyperalgesia.

Address correspondence to: Dr. Tony L. Yaksh, Anesthesiology Research Laboratory–0818, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0818. E-mail: tyaksh{at}ucsd.edu