Bradykinin-induced nociceptor sensitization to heat is mediated by cyclooxygenase products in isolated rat skin

Eur J Neurosci. 2001 Jul;14(2):210-8. doi: 10.1046/j.0953-816x.2001.01651.x.


Bradykinin can excite C-polymodal nociceptors and sensitize them to heat and it can also enhance prostaglandin synthesis, but it is unclear whether these effects are causally related. The role of cyclooxygenase products was investigated using two enantiomers of the cyclooxygenase inhibitor flurbiprofen of which S(+)- is more potent than R(-)-flurbiprofen. Single-unit activity was recorded from mechano-heat-sensitive, polymodal C-fibers in the isolated rat skin-saphenous nerve preparation. Bradykinin pretreatment (10 microM, 5 min) induced a 219 +/- 26% increase in the number of spikes evoked by noxious heat stimulation and a drop in the heat threshold by 5.2 +/- 0.6 degrees C in a fully reproducible manner. S(+)-flurbiprofen (1 microM) abolished the bradykinin-induced heat sensitization but did not alter the unconditioned heat response itself. Under R(-)-flurbiprofen (1 microM) bradykinin still induced a significant heat sensitization which was reduced by 33 +/- 21% (P = 0.11) of its previous extent; this effect may be due to the limited purity of the enantiomer preparation or to a cyclooxygenase-independent action of flurbiprofen. The heat sensitization suppressed by S(+)-flurbiprofen could be significantly restored (to 43 +/- 12%) by addition of PGE(2) plus PGI(2) (10 microM both) to bradykinin. Neither S(+)- nor R(-)-flurbiprofen had an influence on the magnitude of the excitatory effect of bradykinin. It is concluded that (i) cyclooxygenase products are the main mediators of nociceptor sensitization to heat following bradykinin treatment in the isolated rat skin; (ii) PGE(2)/I(2) are essential but perhaps not the only relevant cyclooxygenase products involved and (iii) neither S(+)- nor R(-)-flurbiprofen inhibit the unconditioned noxious heat response and the excitatory bradykinin response of the polymodal C-nociceptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Bradykinin / metabolism
  • Bradykinin / pharmacology*
  • Cyclooxygenase Inhibitors / pharmacology
  • Drug Interactions / physiology
  • Flurbiprofen / pharmacology
  • Hyperalgesia / enzymology*
  • Hyperalgesia / physiopathology
  • Male
  • Nerve Fibers / drug effects
  • Nerve Fibers / enzymology*
  • Nociceptors / drug effects
  • Nociceptors / enzymology*
  • Pain / enzymology
  • Pain / physiopathology
  • Peripheral Nerves / drug effects
  • Peripheral Nerves / enzymology
  • Prostaglandin-Endoperoxide Synthases / drug effects
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Prostaglandins / biosynthesis*
  • Prostaglandins / pharmacology
  • Rats
  • Rats, Wistar
  • Skin / enzymology
  • Skin / innervation*
  • Skin / physiopathology
  • Thermosensing / drug effects
  • Thermosensing / physiology


  • Cyclooxygenase Inhibitors
  • Prostaglandins
  • Flurbiprofen
  • Prostaglandin-Endoperoxide Synthases
  • Bradykinin