Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway.

Abstract

Using a combined pharmacological and gene-deletion approach, we have delineated a novel mechanism of neurokinin-1 (NK-1) receptor-dependent hyperalgesia induced by proteinase-activated receptor-2 (PAR2), a G-protein-coupled receptor expressed on nociceptive primary afferent neurons. Injections into the paw of sub-inflammatory doses of PAR2 agonists in rats and mice induced a prolonged thermal and mechanical hyperalgesia and elevated spinal Fos protein expression. This hyperalgesia was markedly diminished or absent in mice lacking the NK-1 receptor, preprotachykinin-A or PAR2 genes, or in rats treated with a centrally acting cyclooxygenase inhibitor or treated by spinal cord injection of NK-1 antagonists. Here we identify a previously unrecognized nociceptive pathway with important therapeutic implications, and our results point to a direct role for proteinases and their receptors in pain transmission.

• Authors: N Vergnolle, N W Bunnett, K A Sharkey, V Brussee, S J Compton, E F Grady, G Cirino, N Gerard, A I Basbaum, P Andrade-Gordon, M D Hollenberg, J L Wallace
• Journal: Nature medicine (Nat Med) Vol. 7 Issue 7 Pg. 821-6 (Jul 2001) ISSN: 1078-8956 [Print] United States
• PMID: 11433347 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Prostaglandins
• Receptor, PAR-2
• Receptors, Neurokinin-1
• Receptors, Thrombin
• Substance P

Topics

• Animals
• Gene Expression Regulation (drug effects)
• Genes, fos
• Hyperalgesia (metabolism)
• Inflammation
• Male
• Mice
• Mice, Knockout
• Pain (metabolism)
• Prostaglandins (physiology)
• Rats
• Rats, Wistar
• Receptor, PAR-2
• Receptors, Neurokinin-1 (genetics, physiology)
• Receptors, Thrombin (agonists, metabolism)
• Spinal Cord (drug effects, metabolism)
• Substance P (physiology)