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.
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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.)
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Chemical References |
- Prostaglandins
- Receptor, PAR-2
- Receptors, Neurokinin-1
- Receptors, Thrombin
- Substance P
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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)
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