Inflammatory hyperalgesia induced by zymosan in the plantar tissue of the rat: effect of kinin receptor antagonists

The Randall-Selitto paradigm (maximal tolerated pressure externally applied by a mechanical device) was used to develop a rat model of localized infla mmatory hyperalgesia in order to compare the analgesic effects of bradykini n (BK) B-1 and B-2 receptor antagonists and of a non-steroidal anti-inflamm atory drug (NSAID). Intra-plantar injection of zymosan (12.5 mg per paw) in duced a considerable inflammation as evidenced from gross and histological evaluation and a mechanical hyperalgesia at 6 h. The contra-lateral paw of zymosan-treated animals or saline vehicle-injected paws did not exhibit a d ecreased pressure tolerance, relative to pre-injection measurements. Since the B-1 receptor may be induced under inflammatory situations, we examined the amount of corresponding mRNA using quantitative RT-PCR. We found a sign ificant increase of B-1 receptor mRNA in the zymosan - but not the saline-i njected paw at 6 h. Drugs were given subcutaneously 2 h before the 6 h read ings to test their analgesic potential. The kinin B-1 receptor antagonists [Leu(8)]des-Arg(9)-BK (3-30 nmol/kg) and R-715 (100 nmol/kg), the B-2 recep tor antagonists Hoe 140 (15 nmol/kg) and LF 16.0687 (3 and 10 mg/kg), as we ll as the NSAID diclofenac sodium (1 and 3 mg/kg) significantly reversed zy mosan-induced hyperalgesia, We conclude that zymosan-induced hyperalgesia i s a model suitable for the rapid evaluation of analgesic drugs with a perip heral site of action interfering either with kinin receptors or with prosta noid formation. In this regard, results of the present study confirm that b locking kinin B-1 receptors is a novel approach for treatment of inflammato ry pain. (C) 2000 Elsevier Science B.V. All rights reserved.