warrant study for the treatment of chronic cough in humans. Blood pressure Activation of EP3 receptors contracts vascular beds including rat mesentery artery, rat tail artery, guinea-pig aorta, rodent and human pulmonary artery, and murine renal and brain vasculature. Mice depleted of EP3 are partially protected from brain injury consequential to experimentally induced cerebral ischemia. Furthermore, rodent studies indicate that agonist-induced activation of EP3 in the brain by intra-cerebroventricular injection of PGE2 or selective EP3 agonist cause hypertension; a highly selective EP3 receptor antagonist blocked this PGE2-induced response. These studies, which examine a sympatho-excitatory response (i.e. responses wherein brain excitation such as stroke raises blood pressure) suggest that certain hypertension responses in humans are mediated, at least in part, by EP3. Vascular permeability Model studies indicate that PG2 (but not specific antigens or IgE cross-linkage) stimulates mouse and human mast cells to release histamine by an EP3-dependent mechanism. Furthermore, EP3-deficient mice fail to develop increased capillary permeability and tissue swelling in response to EP3 receptor agonists and the metabolic precursor to PGE2, arachidonic acid. It is suggested, based on these and other less direct studies, that PGE2-EP3 signaling may be responsible for the skin swelling and edema provoked by topical 5-aminolaevulinic acid photodynamic therapy, contact with chemical irritants, infection with pathogens, and various skin disorders in humans. Blood clotting Activation of EP3 receptors on the blood platelets of mice, monkeys, and humans enhances their aggregation, degranulation, and blood clot-promoting responsiveness to a wide array of physiological (e.g. thrombin) and pathological (e.g. atheromatous plaques. (In contrast, activation of either the EP2 or EP3 receptor inhibits platelet activation) Inhibition of EP3 with the selective EP3 receptor antagonist, DG-041, has been shown to prevent blood clotting but not to alter hemostasis or blood loss in mice and in inhibit platelet activation responses in human whole blood while not prolonging bleeding times when given to human volunteers. The drug has been proposed to be of potential clinical use for the prevention of blood clotting while causing little or no bleeding tendencies. Pain EP3 deficient mice exhibit significant reductions in: hyperalgesic writhing (i.e. squirming) responses to acetic acid administration; acute but not chronic Herpes simplex infection-induced pain; and HIV-1 Envelope glycoprotein GP120 intrathecal injection-induced tactile allodynia. Furthermore, a selective EP3 agonist, ONO-AE-248, induces hyperalgesia pain in wild type but not EP3-deficient mice. While pain perception is a complex phenomenon involving multiple causes and multiple receptors