The prostaglandin E-2 EP1 receptor mediates pain perception and regulates blood pressure

The lipid mediator prostaglandin E2 (PGE(2)) has diverse biological activit y in a variety of tissues, Four different receptor subtypes (EP1-4) mediate these nide-ranging effects. The EP-receptor subtypes differ in tissue dist ribution, ligand-binding affinity, and coupling to intracellular signaling pathways. To identify the physiological roles for one of these receptors, t he EP1 receptor, we generated EP1-deficient (EP1(-/-)) mice using homologou s recombination in embryonic stem cells derived from the DBA/1lacJ strain o f mice. The EP1(-/-) mice are healthy and fertile, without any overt physic al defects. However, their pain-sensitivity responses, tested in two acute prostaglandin-dependent models, were reduced by approximately 50%. This red uction in the perception of pain was virtually identical to that achieved t hrough pharmacological inhibition of prostaglandin synthesis in wild-type m ice using a cyclooxygenase inhibitor. In addition, systolic blood pressure is significantly reduced in EP1 receptor-deficient mice and accompanied by increased renin-angiotensin activity especially in males, suggesting a role for this receptor in cardiovascular homeostasis. Thus, the EP1 receptor fo r PGE(2) plays a direct role in mediating algesia and in regulation of bloo d pressure.