Effects of a novel selective agonist for prostaglandin receptor subtype EP4 on hyperalgesia and inflammation in monoarthritic model.
BACKGROUND
Cytokines have crucial role in the development and maintenance of inflammation and pain in arthritis. Activation of prostaglandin receptor subtype EP(4) suppresses cytokine production in immune cells. The purpose of this study was to evaluate whether a novel EP(4) agonist would be able to suppress thermal and mechanical hyperalgesia and paw swelling in acute and chronic phases in rat monoarthritic model.


METHODS
Monoarthritis was induced by an injection of complete Freund's adjuvant (CFA) intracapsularly into the tibiotarsal joint of the rats. Withdrawal latencies to thermal stimulation on the hind paw, withdrawal thresholds to mechanical stimulation, paw volume, and ankle diameter were measured 24 h and 4 weeks after the CFA injection. A novel selective EP(4) receptor agonist, ONO-AE1-329 (10, 25, or 50 microg) or saline was administered intracapsularly into the joint.


RESULTS
Withdrawal latencies and withdrawal thresholds were significantly (P < 0.05) shortened and decreased, respectively, on the arthritic side but not on the contralateral side 24 h and 4 weeks after the CFA injection. In addition, significant (P < 0.05) increases in paw volume and ankle diameter on the arthritic side were observed. Intracapsularly administered ONO-AE1-329 showed significant (P < 0.05) inhibition of thermal and mechanical hyperalgesia and significant (P < 0.05) decrease in paw volume and ankle diameter in a dose-dependent manner at 24 h and 4 weeks after CFA.


CONCLUSIONS
Intracapsular administration of EP(4) receptor agonist effectively inhibited mechanical and thermal hyperalgesia and inflammatory reactions in acute and chronic monoarthritis. An EP(4) agonist would be a potential strategy for inflammatory pain in arthritis.
Omote
Keiichi
K
Department of Anesthesiology, Sapporo Medical University School of Medicine, Chuoku, Sapporo, Japan. komote@sapmed.ac.jp
Kawamata
Tomoyuki
T
Nakayama
Yoshito
Y
Yamamoto
Hiroki
H
Kawamata
Mikito
M
Namiki
Akiyoshi
A
D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use*; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D016207:Cytokines / Q000096:biosynthesis; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D008738:Methyl Ethers / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000502:physiology; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018712:Analgesics, Non-Narcotic; D016207:Cytokines; D008738:Methyl Ethers; C461399:ONO-AE1-329; C545652:Ptger4 protein, rat; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha; D005620:Freund's Adjuvant