Zaltoprofen, a non-steroidal anti-inflammatory drug, inhibits bradykinin-induced pain responses without blocking bradykinin receptors

Zaltoprofen, a preferential COX-2 inhibitor, exhibited a potent inhibitory action on the nociceptive responses induced by a retrograde infusion of bradykinin into the right common carotid artery in rats. However, other COX-2 preferential inhibitors such as meloxicam and etodolac did not exhibit any apparent action, and also, preferential COX-1 inhibitors mofezolac and indomethacin, COX-1 and COX-2 inhibitor loxoprofen sodium showed a weak effect. These non-steroidal anti-inflammatory drugs (NSAIDs) except for zaltoprofen, strongly inhibited an acetic acid-induced writhing response related to PGs based on COX-1, at lower doses. Zaltoprofen had a moderate inhibitory effect compared with those of the above-mentioned NSAIDs. These results suggest that the inhibitory effect of zaltoprofen on bradykinin-induced nociceptive responses is not explainable by the inhibition of cyclooxygenase (COX). So, we examined the inhibitory effect of zaltoprofen on bradykinin-induced nociceptive responses by performing several in vitro experiments. Zaltoprofen did not bind to B1 and B2 receptors in a radio-ligand binding assay. In the cultured dorsal root ganglion cells of mature mice, zaltoprofen completely inhibited the bradykinin-induced increase of [Ca2+]i, which was inhibited by B2 antagonist D-Arg-[Hyp3, Thi5,8, D-Phe7]-bradykinin, but not by B1 antagonist. In addition, the inhibition of zaltoprofen on the increase of [Ca2+]i was observed even under extracellular Ca2+-free conditions. The above results suggest that zaltoprofen produces an analgesic action on bradykinin-induced nociceptive responses by blocking the B2 receptor-mediated pathway in the primary sensory neurons. Taken together, these results suggest that zaltoprofen may serve as a potent and superior analgesic for the treatment of pain.