Oral anti-hyperalgesic and anti-inflammatory activity of NK 1 receptor antagonists in models of inflammatory hyperalgesia of the guinea-pig

Abstract

The oral analgesic and anti-inflammatory activity of NK 1 antagonists with species preference for the human receptor were assessed in (1) the carrageenan-induced inflammatory hyperalgesia and (2) Freund's complete adjuvant (FCA)-induced extravasation in the knee joint models of the guinea-pig, respectively. Mechanical hyperalgesia was determined by measuring the withdrawal threshold to a noxious mechanical stimulus applied to the paw and thermal hyperalgesia 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 latencies from 19±0.4 to 4.7±0.9 s as determined 4 h after injection. The hyperalgesia persisted for over 24 h. The NK 1 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-hyperalgesic effect of SDZ NKT 343 and RPR100893 peaked at 3 h while SR140333 produced 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 >100 mg kg −1, respectively. In thermal hyperalgesia, SDZ NKT 343 produced a significantly weaker anti-hyperalgesic effect with a peak of 25% reversal. The D 30 value for SDZ NKT 343 was 3.89 mg kg −1. For comparison, morphine inhibited the carrageenan-induced mechanical and thermal hyperalgesia with an ED 50 of 1.85 and 2.51 mg kg −1 s.c., respectively. When tested up to 300 mg kg −1 p.o., aspirin reduced carrageenan-induced mechanical and thermal hyperalgesia by 55.0 and 45.2%, respectively. In addition to the anti-hyperalgesic effects of NK 1 receptor antagonists, the effects of SDZ NKT 343 and RPR100893 on plasma protein extravasation were measured in the FCA-treated knee joint of the guinea-pig. SDZ NKT 343 reversed plasma protein extravasation 2 h after administration by 60% at the oral dose of 30 mg kg −1. RPR100893 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 hyperalgesia in the guinea-pig may be predictive of analgesic activity of NK 1 receptor antagonists in man. NK 1 receptor antagonists are active anti-hyperalgesic drugs in both mechanical and thermal hyperalgesia in the guinea-pig. In addition they inhibit plasma protein extravasation in the same species. The variability of in vivo potency and efficacy of the NK 1 receptor antagonists in the mechanical hyperalgesia model is difficult to interpret as all compounds are highly effective at blocking the NK 1 receptor in guinea-pig tissues. Amongst several possibilities, differences in pharmacokinetics may explain discrepancies.