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

Nat Med. 2001 Jul;7(7):821-6. doi: 10.1038/89945.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • Receptors, Neurokinin-1 / physiology
  • Receptors, Thrombin / agonists
  • Receptors, Thrombin / metabolism*
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Substance P / physiology


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