The effects of bradykinin and sequence-related analogs on the response properties of cutaneous nociceptors in monkeys

Adil A. Khan, Srinivasa N. Raja, Donald C. Manning, James N. Campbell, Richard A. Meyer

Research output: Contribution to journalArticlepeer-review

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[Hyp3DPhe7]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°C increments, from 41° to 49°C. Intradermal injections of vehicle (neutral normal saline) failed to alter the heat response of CMHs. Bradykinin (10 nmol in 10 μ1) 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° to 42.7 ± 0.5°C (mean ± SEM, p < 0.02), and the total response to the heat test sequence increased by 87% (p < 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 μ1) 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. In contrast to the findings in CMHs, only 2 of the 15 AMHs (1 each with B1 and B2 analogs) were sensitized to heat. These results indicate that the specific bradykinin analogs reported to have antagonistic properties in some algesic models have agonist-like effects on CMHs in monkeys and may not be useful as peripherally acting analgesics.

Original languageEnglish (US)
Pages (from-to)97-106
Number of pages10
JournalSomatosensory & Motor Research
Volume9
Issue number2
DOIs
StatePublished - 1992

Keywords

  • Bradykinin
  • Bradykinin analogs
  • Hyperalgesia
  • Inflammation
  • Nociceptors
  • Pain
  • Primary afferents
  • Sensitization

ASJC Scopus subject areas

  • Physiology
  • Sensory Systems

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