Effect of Intra-articular 4-(S)-Amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl} piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132), a Kinin B2 Receptor Antagonist, on Nociceptive Response in Monosodium Iodoacetate-Induced Experimental Osteoarthritis in Rats

The present study was designed to investigate the role of bradykinin (BK) in the knee joint osteoarthritis induced by intra-articular (i.ar.) administration of monosodium iodoacetate (MIA) in the rat, and to determine the efficacy of the kinin B₂ receptor antagonists, 4-(S)-amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl} piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132) and icatibant, in reducing pain. Rats received MIA (1 mg/25 μl i.ar.) in the right knee. MEN16132, icatibant (1, 3, and 10 μg/25 μl i.ar.), or saline were administered 7 days after MIA treatment, and their antinociceptive effect was observed for 2 weeks. MEN16132 induced a marked and sustained reduction of incapacitation produced by MIA, approximately 56% inhibition of pain at 3 μg/knee. MEN16132 analgesia was more potent and longer lasting, up to 10 days, than icatibant. MEN16132 (3 μg/knee), at different time points from MIA treatment in separate groups of animals, produced comparable maximal antinociceptive effects, whereas the pain response induced by MIA was unaffected if MEN16132 (10 μg/knee) was administered in the contralateral knee. Indomethacin at high doses (100–625 μg/knee) inhibited by approximately 40% but with a short duration the MIA-induced pain. MIA treatment produced a significant increase of BK and prostaglandin E₂ (PGE₂) metabolite levels in synovial fluid up to 21 days, and PGE₂ metabolite levels were reduced almost to basal values by MEN16132. In conclusion the potent and long-lasting analgesic effect of MEN16132 in MIA-induced osteoarthritis indicates an important role for BK in osteoarthritic pain, and suggests that MEN16132 can be a candidate for the treatment of this chronic disease.