models; and g) suppresses sensory Dorsal root ganglion neurons from signaling inflammation-induced pain (i.e. allodynia and hyperalgesia) and has been used successfully to block the osteoarthritis pain in dogs. Gastrointestinal tract EP4 receptors are highly expressed in the small intestine and colon. Mice lacking this receptor or treated with a selective EP4 antagonist proved to be far more susceptible to the development of dextran sodium sulphate (DSS)-induced colitis and to be protected from developing the colitis by pre-treatment with EP4-selective agonists (ONO-AE1-734 and AGN205203). The DDS-inflicted lesions were associated with defective colon mucosa barrier function along with the overexpression of genes mediating inflammatory responses and under-expression of genes involved in mucosal repair and remodeling. EP4 thus appears to serve anti-inflammatory and protective functions in the colon and agonists of this receptor may be useful for treating inflammatory bowel diseases such as ulcerative colitis. Activation of EP4 stimulates duodenum epithelial cells to secrete bicarbonate (HCO3-) in mice and humans; this response neutralizes the acidic fluid flowing from the stomach thereby contributing to the process of intestinal ulcer healing. Activators of this receptor therefore may useful as anti-ulcer drugs. Bone Studies in mice found that the PGE2-EP4 pathway induces osteoclast (i.e. cells responsible for bone absorption) to differentiate from precursor cells and is required for IL-1beta-, Tumor necrosis factor alpha-, and basic fibroblast growth factor-induced osteoclast formation; bone taken from EP4(-/-) mice to re-absorb bone when induced to do so and the infusion of PGE2 into mice failed to stimulate bone absorption. Furthermore, the infusion of selective EP4 agonists into mice stimulated increases in the number of bone osteoclasts and osteoblasts as well as increases in bone density. These studies indicate that the EP4 receptor mediates bone remolding in mice and, it is suggested, other animals including humans. Heart In mice, EP4 receptor agonists reduce the acute rejection of transplanted hearts, prolong the survival of heart-transplanted animals, and reduce cardiac damage in a model of ischemic reperfusion injury but also stimulate cardiac hypertrophy accompanied by poor cardiac function. EP4 receptor-depleted mice exhibit more severe cardiac damage in experimental models of myocardial infarction and ischemic reperfusion injury but also develop cardiac hypertrophy with poor cardiac function. Cardiac specific EP4 deficiency using Site-specific recombination by the Cre recombinase method to inactivate EP4 only in cardiac muscle causes a somewhat different form of cardiac disease, dilated cardiomyopathy, that develops within 23–33 weeks after birth in