Blockade of nociceptive sensory afferent activity of the rat knee joint by the bradykinin B2 receptor antagonist fasitibant.

Abstract

OBJECTIVE:

The aim of this study was to determine in intact and inflamed knee joints of the rat, the effect of the bradykinin (BK) B2 receptor antagonist fasitibant (MEN16132) on nociceptor mechanosensitivity and hyperalgesia.

METHODS:

Joint afferent sensory fibers of the medial articular nerve of anesthetized animals were electrophysiologically recorded, measuring nerve impulse activity evoked by passive innocuous and noxious movements of the joint, in intact and kaolin and carrageenan-injected joints. Knee joints of rats were also acutely inflamed by intra-articular injection of carrageenan alone. Long term duration of fasitibant antinociceptive effects were behaviorally evaluated using the incapacitance test.

RESULTS:

BK (100 μM) injected into the saphenous artery, induced excitation and sensitization of multi- and single unit recordings. Fasitibant (300 μM) injected prior to BK, reduced its excitatory effects as well as the overall increase of movement-evoked activity resulting from repeated injections of BK. Fasitibant did not affect movement-evoked activity of sensory fibers of intact, non-inflamed knee joints. Intra-articular fasitibant (100 μg/knee) significantly reduced the carrageenan-induced inflammatory hyperalgesia measured with the incapacitance test up to four days after treatment. This antinociceptive effect was not obtained with systemic endovenous injection of the drug.

CONCLUSIONS:

Fasitibant prevents B2 receptor-mediated activation and sensitization of peripheral joint afferents and the ensuing inflammatory hyperalgesia, and may be a useful, novel drug for arthritis pain treatment.

• Authors: A Gomis, S Meini, A Miralles, C Valenti, S Giuliani, C Belmonte, C A Maggi
• Journal: Osteoarthritis and cartilage (Osteoarthritis Cartilage) Vol. 21 Issue 9 Pg. 1346-54 (Sep 2013) ISSN: 1522-9653 [Electronic] England
• PMID: 23973149 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Chemical References

• (4-amino-5-(4-(4-(2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido)tetrahydro-2H-4-pyranoylcarbonyl)piperazino)-5-oxopentyl)(trimethyl)ammonium
• Bradykinin B2 Receptor Antagonists
• Sulfonamides
• Ornithine

Topics

• Action Potentials (physiology)
• Animals
• Arthralgia (drug therapy, physiopathology)
• Arthritis, Experimental (drug therapy, physiopathology)
• Behavior, Animal (drug effects)
• Bradykinin B2 Receptor Antagonists
• Disease Models, Animal
• Injections, Intra-Articular
• Knee Joint (drug effects, innervation)
• Male
• Neurons, Afferent (drug effects, physiology)
• Nociceptors (drug effects, physiology)
• Ornithine (analogs & derivatives, pharmacology)
• Osteoarthritis, Knee (drug therapy, physiopathology)
• Rats
• Rats, Wistar
• Sulfonamides (pharmacology)
• Treatment Outcome