The Effects of Bradykinin and Sequence-Related Analogs on the Response Properties of Cutaneous Nociceptors in Monkeys

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Abstract
The endogenous peptide bradykinin is found in plasma and inflammatory exudates and has been implicated as a chemical mediator of inflammatory pain and hyperalgesia. Two subtypes of bradykinin receptors, B1 and B2, have been described, and antagonists for the receptor subtypes have been synthesized. The bradykinin analogs [desArg9,Leu8]BK and DArg[Hyp3,DPhe7]BK have been reported to have antagonist activity at the B1 and B2 bradykinin receptors in smooth muscle, respectively. Behavioral studies in rats indicate that the bradykinin analogs can block the algesic effects of bradykinin. We wished to determine the effects of bradykinin and the bradykinin analogs (B1 and B2 analogs, respectively) on cutaneous nociceptors in the monkey. In addition, we wished to determine the type of bradykinin receptor that mediates the sensitizing effects of bradykinin. Recordings were made from single C-fiber and A-fiber nociceptive afferents (CMHs and AMHs) that innervated hairy skin. Heat sensitivity before and after the injections was determined with a heat test sequence consisting of stimuli that ranged, in 1 degree C increments, from 41 degrees to 49 degrees C. Intradermal injections of vehicle (neutral normal saline) failed to alter the heat response of CMHs. Bradykinin (10 nmol in 10 microliters) evoked activity in 6 of 10 CMHs and sensitized all the fibers to heat stimuli. After the bradykinin injection, the mean heat threshold of the CMHs decreased from 44 +/- 0.5 degrees to 42.7 +/- 0.5 degrees C (mean +/- SEM, p less than 0.02), and the total response to the heat test sequence increased by 87% (p less than 0.002). In a related psychophysical study in human volunteers, the same dose of bradykinin resulted in a comparable (115%) increase in ratings of pain (Manning et al., 1991). Bradykinin also evoked activity in 10 of 17 AMHs and sensitized 8 AMHs to heat stimuli. Bradykinin failed to alter the threshold for activation of CMHs to mechanical stimuli as measured by application of von Frey hairs to the receptive field. In contrast to bradykinin, intradermal injection of the B1 and B2 analogs (10 nmol in 10 microliters) evoked activity in 2 of 6 and 0 of 5 CMHs, respectively. A noteworthy finding was that both analogs enhanced the response of CMHs to heat stimuli by 50% (B1 analog, 1.5 +/- 0.1; B2 analog, 1.5 +/- 0.2). The B1 (n = 10) and B2 (n = 5) analogs did not evoke activity in any of the 15 AMHs tested.(ABSTRACT TRUNCATED AT 400 WORDS)