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

• Published in: Neuroscience research 2006-04, Vol.54 (4), p.288-294
• Main Authors: Hirate, Kenji, Uchida, Aoi, Ogawa, Yuki, Arai, Tomoko, Yoda, Kentaro
• Format: Article
• Language: English
• Subjects: Acetic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Benzopyrans - pharmacology; Bradykinin; Bradykinin - physiology; Bradykinin Receptor Antagonists; Calcium - metabolism; Cells, Cultured; Cyclooxygenase Inhibitors - pharmacology; Dorsal root ganglion; Ganglia, Spinal - cytology; Ganglia, Spinal - metabolism; Guinea Pigs; In Vitro Techniques; Male; Mice; Mice, Inbred ICR; Nociceptive response; NSAIDs; Pain - chemically induced; Pain - drug therapy; Pain - metabolism; Propionates - pharmacology; Radioligand Assay; Rats; Rats, Wistar; Receptor, Bradykinin B1 - metabolism; Receptor, Bradykinin B2 - metabolism; Receptors, Bradykinin - metabolism; Zaltoprofen
• ISSN: 0168-0102; 1872-8111
• DOI: 10.1016/j.neures.2005.12.016

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 B 1 and B 2 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 [Ca 2+] i, which was inhibited by B 2 antagonist D-Arg-[Hyp 3, Thi 5,8, D-Phe 7]-bradykinin, but not by B 1 antagonist. In addition, the inhibition of zaltoprofen on the increase of [Ca 2+] i was observed even under extracellular Ca 2+-free conditions. The above results suggest that zaltoprofen produces an analgesic action on bradykinin-induced nociceptive responses by blocking the B 2 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.