Intrathecal protease-activated receptor stimulation produces thermal hyperalgesia through spinal cyclooxygenase activity.

Abstract

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-NH(2) and the PAR 2-derived peptide SLIGRL both stimulated PGE(2) 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-NH(2) and SLIGRL both produced thermal hyperalgesia. Consistent with their effects on spinal PGE(2), 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.

• Authors: Lee Koetzner, Joshua A Gregory, Tony L Yaksh
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 311 Issue 1 Pg. 356-63 (Oct 2004) ISSN: 0022-3565 [Print] United States
• PMID: 15175421 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Isoenzymes
• Membrane Proteins
• Peptides
• Receptors, Proteinase-Activated
• Cyclooxygenase 1
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Ptgs1 protein, rat
• Thrombin
• Dinoprostone

Topics

• Animals
• Behavior, Animal (drug effects)
• Cyclooxygenase 1
• Cyclooxygenase 2
• Dinoprostone (metabolism)
• Hyperalgesia (enzymology, metabolism)
• Isoenzymes (metabolism)
• Male
• Membrane Proteins
• Microdialysis
• Peptides (pharmacology)
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Proteinase-Activated (metabolism, physiology)
• Spinal Cord (enzymology)
• Thrombin (pharmacology)