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 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 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-hyperalgesic effect of SDZ NKT 343 and RPR100893 peaked at 3 h while SR140333 produced maximal reversal at 1 h after oral administration. D₃₀ values indicated significant differences between the potency of these compounds. SDZ NKT 343 was by far the most potent anti-hyperalgesic agent (D₃₀: 1.1 mg kg^-1). The D₃₀ 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 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 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 NK₁ 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 NK₁ receptor antagonists in man. NK₁ 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 NK₁ receptor antagonists in the mechanical hyperalgesia model is difficult to interpret as all compounds are highly effective at blocking the NK₁ receptor in guinea-pig tissues. Amongst several possibilities, differences in pharmacokinetics may explain discrepancies. (C) 2000 International Association for the Study of Pain.