Journal
NATURE MEDICINE
Volume 7, Issue 7, Pages 821-826Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/89945
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Funding
- NHLBI NIH HHS [HL 41587] Funding Source: Medline
- NIDDK NIH HHS [DK 43207, DK 39957, DK 57840, DK 52388] Funding Source: Medline
- NINDS NIH HHS [NS 14627] Funding Source: Medline
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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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