Oral anti-hyperalgesic and anti-inflammatory activity of NK(1) receptor antagonists in models of inflammatory hyperalgesia of the guinea-pig.
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.
Campbell
Elizabeth A
EA
Novartis Institute for Medical Sciences, 5 Gower Place, London WC1E 6BN, UK St. Bartholomew's School of Medicine, London, UK.
Gentry
Clive
C
Patel
Sadhana
S
Kidd
Bruce
B
Cruwys
Simon
S
Fox
Alyson J
AJ
Urban
Laszlo
L
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002351:Carrageenan; D004195:Disease Models, Animal; D005260:Female; D005620:Freund's Adjuvant; D006168:Guinea Pigs; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D007211:Indoles / Q000627:therapeutic use; D054833:Isoindoles; D008297:Male; D009281:Naphthalenes / Q000627:therapeutic use*; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000627:therapeutic use; D011392:Proline / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011812:Quinuclidines / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; D007211:Indoles; D054833:Isoindoles; D009281:Naphthalenes; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011812:Quinuclidines; C113385:SDZ NKT 343; C085215:SR 140333; C089835:RPR 100893; D002351:Carrageenan; D005620:Freund's Adjuvant; D011392:Proline