Preemptive analgesia by zaltoprofen that inhibits bradykinin action and cyclooxygenase in a post-operative pain model.
The post-operative pain state results from a barrage of primary afferent inputs exposed to products of tissue damage such as bradykinin and prostaglandins and the central sensitization by the continuing inputs. This provides the rationale for preemptive analgesia, whereby the blockade of primary afferent inputs prior to injury may result in a reduction of post-operative pain. 2-(10,11-dihydro-10-oxo-dibenzo[b,f]thiepin-2-yl) propionic acid (zaltoprofen) is a unique compound that inhibits cyclooxygenase (COX) and exhibits anti-bradykinin activity. The present study evaluated the preemptive analgesic effect of zaltoprofen in a post-operative pain model produced by plantar incision. When orally, but no intrathecally, administered 30 min prior to incision, zaltoprofen significantly increased the withdrawal threshold 2 h and 1-3 days after incision at 10 mg/kg. While the bradykinin B1 antagonist des-Arg10-HOE-140, the selective COX-1 inhibitor SC-560, and the selective COX-2 inhibitor celecoxib did not affect post-operative pain, the B2 antagonist HOE-140 dose-dependently relieved the post-operative pain at 2-200 microg/kg with a time course similar to that of zaltoprofen. The B2 receptor mRNA was expressed in the hindpaw and the expression did not change before and 24 h after surgery. These results suggest that zaltoprofen produces the preemptive analgesic effect peripherally by blocking the B2 pathway.
Muratani
Tadatoshi
T
Department of Anesthesiology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki 569-8686, Japan.
Doi
Yumi
Y
Nishimura
Wataru
W
Nishizawa
Mikio
M
Minami
Toshiaki
T
Ito
Seiji
S
D000284:Administration, Oral; D000698:Analgesia; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D001578:Benzopyrans / Q000008:administration & dosage*; D001920:Bradykinin / Q000187:drug effects*; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D010149:Postoperative Pain / Q000517:prevention & control*; D011422:Propionates / Q000008:administration & dosage*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D043782:Receptor, Bradykinin B2 / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D016861:Cyclooxygenase Inhibitors; D011422:Propionates; D011720:Pyrazoles; D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; C115461:SC 560; D013449:Sulfonamides; C043940:pyranoprofen; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D001920:Bradykinin