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Article
Nature Medicine  7, 821 - 826 (2001)
doi:10.1038/89945

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

N. Vergnolle1, N.W. Bunnett2, K.A. Sharkey3, V. Brussee4, S.J. Compton1, E.F. Grady2, G. Cirino5, N. Gerard6, A.I. Basbaum7, P. Andrade-Gordon8, M.D. Hollenberg1 & J.L. Wallace1

1  Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada

2  Departments of Surgery and Physiology, University of California, San Francisco, California, USA

3  Department of Physiology & Biophysics, University of Calgary, Calgary, Alberta, Canada

4  Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada

5  Department of Experimental Pharmacology, University of Naples, Naples, Italy

6  Pulmonary Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

7  Departments of Anatomy and Physiology, University of California, San Francisco, California, USA

8  R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania, USA

Correspondence should be addressed to J.L. Wallace wallacej@ucalgary.ca
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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ISSN: 1078-8956
EISSN: 1546-170X
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