Metallopeptidase inhibition potentiates bradykinin-induced hyperalgesia

Pain. 2011 Jul;152(7):1548-1554. doi: 10.1016/j.pain.2011.02.044. Epub 2011 Apr 1.


The neuropeptide bradykinin (BK) sensitizes nociceptor activation following its release in response to inflammatory injury. Thereafter, the bioactivity of bradykinin is controlled by the enzymatic activities of circulating peptidases. One such enzyme, the metalloendopeptidase EC3.4.24.15 (EP24.15), is co-expressed with bradykinin receptors in primary afferent neurons. In this study, using approaches encompassing pharmacology, biochemistry, cell biology, and behavioral animal models, we identified a crucial role for EP24.15 and the closely related EP24.16 in modulating bradykinin-mediated hyperalgesia. Pharmacological analyses indicated that EP24.15 and EP24.16 inhibition significantly enhances bradykinin type-2 receptor activation by bradykinin in primary trigeminal ganglia cultures. In addition, bradykinin-induced sensitization of TRPV1 activation was increased in the presence of the EP24.15/16 inhibitor JA-2. Furthermore, behavioral analyses illustrated a significant dose-response relationship between JA-2 and bradykinin-mediated thermal hyperalgesia. These results indicate an important physiological role for the metallopeptidases EP24.15 and EP24.16 in regulating bradykinin-mediated sensitization of primary afferent nociceptors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bradykinin / adverse effects*
  • Calcium / metabolism
  • Cells, Cultured
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology*
  • Hyperalgesia / chemically induced*
  • Hyperalgesia / enzymology*
  • Inositol Phosphates / metabolism
  • Male
  • Metalloproteases / antagonists & inhibitors
  • Metalloproteases / metabolism*
  • Oligopeptides / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / enzymology
  • TRPV Cation Channels / metabolism
  • Trigeminal Ganglion / cytology


  • Enzyme Inhibitors
  • Inositol Phosphates
  • JA 2 compound
  • Oligopeptides
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • Metalloproteases
  • Bradykinin
  • Calcium