Characterisation and mechanisms of bradykinin-evoked pain in man using iontophoresis

Kathryn J. Paterson*, Laura Zambreanu, David L. H. Bennett, Stephen B. McMahon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Bradykinin (BK) is an inflammatory mediator that can evoke oedema and vasodilatation, and is a potent algogen signalling via the B1 and B2 G-protein coupled receptors. In naive skin, BK is effective via constitutively expressed B2 receptors (B2R), while B1 receptors (B1R) are purported to be upregulated by inflammation. The aim of this investigation was to optimise BK delivery to investigate the algesic effects of BK and how these are modulated by inflammation. BK iontophoresis evoked dose-and temperature-dependent pain and neurogenic erythema, as well as thermal and mechanical hyperalgesia (P < 0.001 vs saline control). To differentiate the direct effects of BK from indirect effects mediated by histamine released from mast cells (MCs), skin was pretreated with compound 4880 to degranulate the MCs prior to BK challenge. The early phase of BK-evoked pain was reduced in degranulated skin (P < 0.001), while thermal and mechanical sensitisation, wheal, and flare were still evident. In contrast to BK, the B1R selective agonist des-Arg9-BK failed to induce pain or sensitise naive skin. However, following skin inflammation induced by ultraviolet B irradiation, this compound produced a robust pain response. We have optimised a versatile experimental model by which BK and its analogues can be administered to human skin. We have found that there is an early phase of BK-induced pain which partly depends on the release of inflammatory mediators by MCs; however, subsequent hyperalgesia is not dependent on MC degranulation. In naive skin, B2R signaling predominates, however, cutaneous inflammation results in enhanced B1R responses.

Original languageEnglish
Pages (from-to)782-792
Number of pages11
JournalPain
Volume154
Issue number6
DOIs
Publication statusPublished - Jun 2013

Keywords

  • Pain
  • Bradykinin
  • Des-Arg9-bradykinin
  • Iontophoresis
  • Mast cell
  • SKIN MAST-CELLS
  • HUMAN FOREARM
  • NEUROPATHIC PAIN
  • B-1 RECEPTORS
  • HYPERALGESIA
  • RAT
  • SENSITIZATION
  • HISTAMINE
  • HUMANS
  • 5-HYDROXYTRYPTAMINE

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