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 inflammatory hyperalgesia in order to compare the analgesic effects of bradykinin (BK) B1 and B2 receptor antagonists and of a non-steroidal anti-inflammatory drug (NSAID). Intra-plantar injection of zymosan (12.5 mg per paw) induced 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 decreased pressure tolerance, relative to pre-injection measurements. Since the B1 receptor may be induced under inflammatory situations, we examined the amount of corresponding mRNA using quantitative RT-PCR. We found a significant increase of B1 receptor mRNA in the zymosan--but not the saline-injected paw at 6 h. Drugs were given subcutaneously 2 h before the 6 h readings to test their analgesic potential. The kinin B1 receptor antagonists [Leu8]des-Arg9-BK (3-30 nmol/kg) and R-715 (100 nmol/kg), the B2 receptor antagonists Hoe 140 (15 nmol/kg) and LF 16.0687 (3 and 10 mg/kg), as well as the NSAID diclofenac sodium (1 and 3 mg/kg) significantly reversed zymosan-induced hyperalgesia. We conclude that zymosan-induced hyperalgesia is a model suitable for the rapid evaluation of analgesic drugs with a peripheral site of action interfering either with kinin receptors or with prostanoid formation. In this regard, results of the present study confirm that blocking kinin B1 receptors is a novel approach for treatment of inflammatory pain.