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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Acknowledgements
We thank D.W. Zochodne for assistance and advice and K. Chapman, L. Oland, M. Saifeddine and C. MacNaughton for technical assistance. This work was supported by grants from the Canadian Institutes of Health Research (to N.V., M.D.H., K.A.S. and J.L.W.), NicOx S.A. (to N.V.) the Johnson & Johnson Focused Giving Program (to N.W.B., M.D.H. and J.L.W.) and from the National Institutes of Health (DK 39957, DK 43207 and DK 57840 to N.W.B.; DK52388 to E.F.G.; HL41587 to N.G.; NS14627 to A.I.B.).
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Vergnolle, N., Bunnett, N., Sharkey, K. et al. Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway. Nat Med 7, 821–826 (2001). https://doi.org/10.1038/89945
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DOI: https://doi.org/10.1038/89945
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