Bradykinin increases the proportion of neonatal rat dorsal root ganglion neurons that respond to capsaicin and protons

A number of studies have examined bradykinin-induced sensitization of primary afferent neurons to mechanical or thermal stimuli. However, bradykinin-induced sensitization to other chemical stimuli has not been systematically addressed. We used primary cultures of dorsal root ganglion neurons from neonatal rats to determine whether bradykinin alters the responsiveness of individual neurons to capsaicin and protons. An increase in the concentration of free intracellular Ca2+ was used as a measure of a response to capsaicin or low pH. Pretreatment with bradykinin (30 nM) increased the proportion of "intermediate-size" (240-320 microm2) dorsal root ganglion neurons that responded to capsaicin (100 nM) or low pH (6.1). However, among "small-size" (160-239 microm2) neurons, bradykinin increased the proportion of neurons that responded to low pH (6.1) but not to capsaicin (10 or 100 nM). Because treatment with arachidonic acid (10 microM) did not mimic the effect of bradykinin and inhibition of cyclo-oxygenase and lipoxygenase with 5,8,11,14-eicosatetraynoic acid (10 microM) did not inhibit the effect of bradykinin on the response to capsaicin, it is not likely that the bradykinin-induced enhancement of neuronal responsiveness is mediated by arachidonic acid or its metabolites in this model. These results support the hypothesis that bradykinin sensitizes primary afferent neurons to other chemicals such as protons that are present in inflamed tissue, particularly by recruiting additional sensory neurons to respond to a given chemical stimulus. An increase in the number of responsive nociceptors that innervate inflamed tissue would contribute to hyperalgesia via spatial summation on spinal neurons in the pathway for pain. Furthermore, since bradykinin enhanced the responsiveness of small-size neurons that responded to protons but not to capsaicin, these data suggest that bradykinin-induced sensitization to protons and capsaicin occur by different mechanisms.