Oral anti-hyperalgesic and anti-in¯ammatory activity of NK 1 receptor antagonists in models of in¯ammatory hyperalgesia of the guinea-pig Elizabeth A. Campbell a , Clive Gentry a , Sadhana Patel a , Bruce Kidd b , Simon Cruwys b , Alyson J. Fox a , Laszlo Urban a, * a Novartis Institute for Medical Sciences, 5 Gower Place, London WC1E 6BN, UK b St. Bartholomew's School of Medicine, London, UK Received 12 October 1999; received in revised form 25 January 2000; accepted 9 March 2000 Abstract The oral analgesic and anti-in¯ammatory activity of NK 1 antagonists with species preference for the human receptor were assessed in (1) the carrageenan-induced in¯ammatory 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 21 p.o., respectively. No further reduction was noted at higher doses (maximum 100 mg kg 21 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 signi®cant 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 21 ). The D 30 values for RPR100893 and SR140333 were estimated to be 17 and .100 mg kg 21 , respectively. In thermal hyperalgesia, SDZ NKT 343 produced a signi®cantly weaker anti-hyperalgesic effect with a peak of 25% reversal. The D 30 value for SDZ NKT 343 was 3.89 mg kg 21 . For comparison, morphine inhibited the carrageenan-induced mechanical and thermal hyperalgesia with an ED 50 of 1.85 and 2.51 mg kg 21 s.c., respectively. When tested up to 300 mg kg 21 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 21 . RPR100893 was signi®cantly less effective with a maximum reversal of 30% at 100 mg kg 21 . In comparison, indomethacin produced a 50% reversal at a 10 mg kg 21 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 ef®cacy of the NK 1 receptor antagonists in the mechanical hyperalgesia model is dif®cult 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. q 2000 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. Keywords: Hyperalgesia; In¯ammation; Guinea-pig; NK 1 receptor antagonists; Anti-hyperalgesia; Gastric erosion 1. Introduction The tachykinins, substance P (SP), neurokinin A (NK-A) and neurokinin B (NK-B), are the preferential endogenous ligands for the NK 1 , NK 2 and NK 3 receptors, respectively. They belong to a family of small peptides that are widely distributed in the central and peripheral nervous systems, where they mediate a broad range of biological activities (Maggi et al., 1993). Substance P is released from both the central and periph- eral terminals of primary afferent C-®bres and has been implicated in the pathophysiology of a variety of diseases involving pain and in¯ammation. In the rat, both NK 1 and NK 2 receptors are implicated during in¯ammation in the modulation of nociceptive transmission in the spinal cord (Thompson et al., 1994). The development of selective NK 1 Pain 87 (2000) 253±263 0304-3959/00/$20.00 q 2000 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. PII: S0304-3959(00)00288-8 www.elsevier.nl/locate/pain * Corresponding author. Tel.: 144-171-333-2126; fax: 144-171-387- 4116. E-mail address: laszlo.urban@pharma.novartis.com (L. Urban).