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 B(2) 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 microl i.ar.) in the right knee.
MEN16132,
icatibant (1, 3, and 10 microg/25 microl 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 microg/knee.
MEN16132 analgesia was more potent and longer lasting, up to 10 days, than
icatibant.
MEN16132 (3 microg/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 microg/knee) was administered in the contralateral knee.
Indomethacin at high doses (100-625 microg/knee) inhibited by approximately 40% but with a short duration the MIA-induced
pain. MIA treatment produced a significant increase of BK and
prostaglandin E(2) (
PGE(2)) metabolite levels in synovial fluid up to 21 days, and
PGE(2) 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.