Oral anti-hyperalgesic and anti-inflammatory activity of NK1 receptor antagonists in models of inflammatory hyperalgesia of the guinea-pig

The oral analgesic and anti-inflammatory activity of NK1 antagonists with s pecies preference for the human receptor were assessed in (1) the carrageen an-induced inflammatory hyperalgesia and (2) Freund's complete adjuvant (FC A)-induced extravasation in the knee joint models of the guinea-pig, respec tively. Mechanical hyperalgesia was determined by measuring the withdrawal threshold to a noxious mechanical stimulus applied to the paw and thermal h yperalgesia as the withdrawal latency to a noxious thermal stimulus applied to the plantar surface. A concentration of 1.0% carrageenan (intraplantar) reduced mechanical thresholds from 124 +/- 5 to 63 +/- 3 g and thermal lat encies from 19 +/- 0.4 to 4.7 +/- 0.9 s as determined 4 h after injection. The hyperalgesia persisted for over 24 h. The NK1 receptor antagonists, SDZ NKT 343, RPR100893 and SR140333, reduced mechanical hyperalgesia by 68, 36 and 27% at a dose of 30 mg kg(-1) p.o., respectively No further reduction was noted at higher doses (maximum 100 mg kg(-1) p.o.). The anti-hyperalges ic effect of SDZ NKT 343 and RPR100893 peaked at 3 h while SR140333 produce d maximal reversal at 1 h after oral administration. D-30 values indicated significant differences between the potency of these compounds. SDZ NKT 343 was by far the most potent anti-hyperalgesic agent (D-30: 1.1 mg kg(-1)). The D-30 values for RPR100893 and SR140333 were estimated to be 17 and > 10 0 mg kg(-1), respectively. In thermal hyperalgesia, SDZ NKT 343 produced a significantly weaker anti-hyperalgesic effect with a peak of 25% reversal. The D30 value for SDZ NKT 343 was 3.89 mg kg(-1). For comparison, morphine inhibited the carrageenan-induced mechanical and thermal hyperalgesia with an ED50 of 1.85 and 2.51 mg kg(-1) s.c., respectively. When tested up to 30 0 mg kg(-1) p.o., aspirin reduced carrageenan-induced mechanical and therma l hyperalgesia by 55.0 and 45.2%, respectively. In addition to the anti-hyp eralgesic effects of NK1 receptor antagonists, the effects of SDZ NKT 343 a nd RPRI00893 on plasma protein extravasation were measured in the FCA-treat ed knee joint of the guinea-pig. SDZ NKT 343 reversed plasma protein extrav asation 2 h after administration by 60% at the oral dose of 30 mg kg(-1). R PR100893 was significantly less effective with a maximum reversal of 30% at 100 mg kg(-1). In comparison, indomethacin produced a 50% reversal at a 10 mg kg(-1) dose. These experiments indicate that the carrageenan-induced hy peralgesia in the guinea-pig may be predictive of analgesic activity of NK1 receptor antagonists in man. NK1 receptor antagonists are active anti-hype ralgesic drugs in both mechanical and thermal hyperalgesia in the guinea-pi g. In addition they inhibit plasma protein extravasation in the same specie s. The variability of in vivo potency and efficacy of the NK1 receptor anta gonists in the mechanical hyperalgesia model is difficult to interpret as a ll compounds are highly effective at blocking the NK1 receptor in guinea-pi g tissues. Amongst several possibilities. differences in pharmacokinetics m ay explain discrepancies. (C) 2000 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.