To investigate the possible contribution of the bradykinin (BK) system to heat-induced substance P (SP) release from the peripheral endings of primary afferent nerves, we used the high molecular weight (HMW) and low molecular weight (LMW) kininogen-deficient rat strain (Brown Norway-Katholiek, B/N-Ka) and the normal rat strain (Brown Norway-Kitasato, B/N-Ki). We found that immersion of the paw of B/N-Ki rats in water of 47 degrees C for 20 min led to significant increases of BK, SP and Evans blue extravasation in the s.c. perfusate, and that similar treatment resulted in significantly lower levels in B/N-Ka rats. Local application of BK (10(-4) M) to the s.c. perfusate and intra-arterial infusion of BK 10(-5) mol/kg) increased Evans blue extravasation and SP release evoked by heat stimulation, respectively, in B/N-Ka rats to similar levels to those in B/N-Ki rats after heat-stimulation without BK treatment. These results indicate that BK released into the extravascular space by noxious stimulation is involved in SP release from the peripheral endings of capsaicin-sensitive primary sensory neurons.