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.

CONCLUSION:

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: N Schuelert, S Just, L Corradini, R Kuelzer, C Bernloehr, H Doods
• Journal: European journal of pain (London, England) (Eur J Pain) Vol. 19 Issue 1 Pg. 132-42 (Jan 2015) ISSN: 1532-2149 [Electronic] England
• PMID: 25088373 (Publication Type: Journal Article)
• Copyright: © 2014 European Pain Federation - EFIC®

Chemical References

• Bradykinin B1 Receptor Antagonists

Topics

• Animals
• Bradykinin B1 Receptor Antagonists (pharmacology, therapeutic use)
• Hyperalgesia (drug therapy, physiopathology)
• Inflammation (drug therapy, physiopathology)
• Male
• Nociceptors (drug effects, physiology)
• Pain Measurement
• Pain Threshold (drug effects)
• Peripheral Nerves (drug effects, physiopathology)
• Rats
• Rats, Wistar
• Spinal Nerves (drug effects, physiopathology)