Altered pain perception and inflammatory response in mice lacking prostacyclin receptor.
Prostanoids are a group of bioactive lipids working as local mediators and include D, E, F and I types of prostaglandins (PGs) and thromboxanes. Prostacyclin (PGI2) acts on platelets and blood vessels to inhibit platelet aggregation and to cause vasodilatation, and is thought to be important for vascular homeostasis. Aspirin-like drugs, including indomethacin, which inhibit prostanoid biosynthesis, suppress fever, inflammatory swelling and pain, and interfere with female reproduction, suggesting that prostanoids are involved in these processes, although it is not clear which prostanoid is the endogenous mediator of a particular process. Prostanoids act on seven-transmembrane-domain receptors which are selective for each type. Here we disrupt the gene for the prostacyclin receptor in mice by using homologous recombination. The receptor-deficient mice are viable, reproductive and normotensive. However, their susceptibility to thrombosis is increased, and their inflammatory and pain responses are reduced to the levels observed in indomethacin-treated wild-type mice. Our results establish that prostacyclin is an antithrombotic agent in vivo and provide evidence for its role as a mediator of inflammation and pain.
Murata
T
T
Department of Pharmacology, Faculty of Medicine, Kyoto University, Sakyo, Japan.
Ushikubi
F
F
Matsuoka
T
T
Hirata
M
M
Yamasaki
A
A
Sugimoto
Y
Y
Ichikawa
A
A
Aze
Y
Y
Tanaka
T
T
Yoshida
N
N
Ueno
A
A
Oh-ishi
S
S
Narumiya
S
S
D000818:Animals; D000991:Antithrombins / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015232:Dinoprostone / Q000494:pharmacology; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D018390:Gene Targeting; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D010146:Pain; D010974:Platelet Aggregation / Q000187:drug effects; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015183:Restriction Mapping; D013927:Thrombosis / Q000517:prevention & control
D000991:Antithrombins; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D011464:Epoprostenol; D015232:Dinoprostone; C043867:cicaprost