title: The bradykinin B1 receptor antagonist BI113823 reverses inflammatory hyperalgesia by desensitization of peripheral and spinal neurons.
abstract: BACKGROUND
  Bradykinin is a neuropeptide released after tissue damage which plays an important role in inflammatory pain. The up-regulation of the bradykinin B1 receptor in response to inflammation makes it an attractive target for drug development. Aim was to investigate if the selective B1 receptor antagonist BI113823 reduces inflammation-induced mechanical hyperalgesia and if the effect is mediated via peripheral and/or spinal B1 receptor antagonism.
  
  
  METHODS
  Electrophysiological recordings of peripheral afferents and spinal neurons were combined with behavioural experiments to better understand the underlying mechanisms of B1 receptor antagonism. Experiments were performed 24 h after injection of complete Freund's adjuvant (CFA) or saline into the paw of Wistar rats. A gene expression analysis for the B1 receptor was performed in different tissues. BI113823 was administered orally or intrathecally to assess effects on CFA-induced hyperalgesia. Peripheral afferents of the saphenous nerve as well as spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were recorded, and mechanosensitivity was measured before and after BI113823 administration.
  
  
  RESULTS
  BI113823 reduced CFA-induced mechanical hyperalgesia when administered orally or intrathecally. An increased B1 receptor gene expression was found in peripheral and spinal neural tissue. BI113823 significantly reduced mechanosensitivity of peripheral afferents and spinal NS neurons, but had no effect on WDR neurons.
  
  
  CONCLUSIONS
  The selective bradykinin B1 receptor antagonist BI113823 reduces CFA-induced mechanical hyperalgesia which is mediated via antagonism of peripheral as well as spinal bradykinin B1 receptors. The selective modulation of CFA-sensitized spinal NS neurons by BI113823 could be a promising property for the treatment of inflammatory pain.
authors.affiliation: Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Schuelert
authors.forename: S
authors.initials: S
authors.lastname: Just
authors.forename: L
authors.initials: L
authors.lastname: Corradini
authors.forename: R
authors.initials: R
authors.lastname: Kuelzer
authors.forename: C
authors.initials: C
authors.lastname: Bernloehr
authors.forename: H
authors.initials: H
authors.lastname: Doods
mesh_terms: D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D009619:Nociceptors / Q000187:drug effects* / Q000502:physiology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010525:Peripheral Nerves / Q000187:drug effects* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D013127:Spinal Nerves / Q000187:drug effects* / Q000503:physiopathology
chemical_list: D065169:Bradykinin B1 Receptor Antagonists