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 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.
Hirate
Kenji
K
Research Laboratories, Nippon Chemiphar Co. Ltd., Misato, Japan. k-hirate@chemiphar.co.jp
Uchida
Aoi
A
Ogawa
Yuki
Y
Arai
Tomoko
T
Yoda
Kentaro
K
D019342:Acetic Acid; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D001920:Bradykinin / Q000502:physiology*; D065168:Bradykinin Receptor Antagonists; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1 / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D018002:Receptors, Bradykinin / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D065168:Bradykinin Receptor Antagonists; D016861:Cyclooxygenase Inhibitors; D011422:Propionates; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; C043940:pyranoprofen; D019342:Acetic Acid; D001920:Bradykinin; D002118:Calcium