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Altered pain perception and inflammatory response in mice lacking prostacyclin receptor

Nature volume 388, pages 678–682 (1997)Cite this article

Abstract

Prostanoids are a group of bioactive lipids working as local mediators1 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 homeostasis2. 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 processes1,3, 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 type4. Here we disrupt the gene for the prostacyclin receptor5 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.

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Figure 1: Targeted disruption of the IP gene and loss of the functional receptor.
Figure 2: Arterial thrombosis in wild-type and IP-deficient homozygous mice.
Figure 3: Inflammatory responses in IP-deficient mice.
Figure 4: Nociceptive responses in IP-deficient mice.

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Acknowledgements

We thank K. Ishikawa and Y. Kataoka for ES cell injeciton and K. Okuyama for secretarial assistance. This work was supported by grants from the Ministry of Education, Science and Culture of Japan, the Japanese Society for Promotion of Sciences, the Uehara Memorial Foundation, the Smoking Research Foundation and the Japanese Foundation on Metabolism and Diseases.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Sakyo, 606-01, Kyoto, Japan

    Takahiko Murata, Fumitaka Ushikubi, Toshiyuki Matsuoka, Masakazu Hirata & Shuh Narumiya

  2. Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Sakyo, 606-01, Kyoto, Japan

    Atsushi Yamasaki, Yukihiko Sugimoto & Atsushi Ichikawa

  3. Fukui Institute for Safety Research, Ono Pharmaceutical Company, Mikuni, 913, Fukui, Japan

    Yoshiya Aze

  4. Division of Molecular and Cellular Immunology, Research Institute Osaka Medical Center for Maternal and Child Health, Izumi, 590-02, Osaka, Japan

    Takashi Tanaka & Nobuaki Yoshida

  5. Department of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, Shirokane, 108, Tokyo, Japan

    Akinori Ueno & Sachiko Oh-ishi

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  1. Takahiko Murata
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Correspondence to Shuh Narumiya.

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Murata, T., Ushikubi, F., Matsuoka, T. et al. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 388, 678–682 (1997). https://doi.org/10.1038/41780

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