The prostaglandin E2 EP1 receptor mediates pain perception and regulates blood pressure

Abstract

IntroductionProstaglandin E2 (PGE 2 ) is produced during inflammatory responses, and increased levels of PGE 2 help mediate some of the cardinal features of inflammation, including pain, edema, and fever (1, 2). PGE 2 exerts its effects through interactions with EP receptors, termed EP1-4 (3). Nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting cyclooxygenase (COX) enzymes and thereby inhibiting prostaglandin production. In the context of this putative mechanism of action, direct cause-and-effect relationships between interruption of specific receptor-mediated signaling pathways and therapeutic actions have not been firmly established. While NSAIDs are effective analgesic agents, certain NSAIDs have a number of troublesome side effects that are due in part to their broad inhibition of a variety of COX products (4,5).Defining the molecular mechanisms underlying both the therapeutic and adverse actions of NSAIDs should provide useful targets for new, more specific therapeutic strategies. Therefore, we focused on a receptor for one of the prostaglandins (PGE 2 ), the EP1 receptor (6). We generated EP1-deficient mice by gene targeting and compared their physiological responses to genetically matched wild-type controls. We find that EP1 -/-animals have reduced nociceptive pain perception as well as altered cardiovascular homeostasis. These results demonstrate the critical actions of EP1 receptors in two physiological functions: pain perception and blood pressure regulation. Methods EP1 targeting vector construction and production of EP1 -/-mice.Mouse genomic clones containing Ptgerep1, mouse gene symbol for EP1 receptor, were isolated from a DBA/1lacJ genomic λ-phage library (Stratagene, La Jolla, California, USA). Long-template PCR was used to amplify 5′and 3′ fragments of the clone using T3 or T7 and EP1-specific primers. A 4.5-kb 5′ fragment and 6.0-kb 3′ fragment were cloned into pCRII vector (Invitrogen Corp., San Diego, California, USA). These fragments were sequence confirmed and subcloned into pHok, a plasmid containing PGK-neo and PGK-thymidine kinase cassettes. The EP1 targeting vector was designed to replace 671 bp of coding sequence with the PGK-neo cassette. This 671-bp coding region was Received for publication March 9, 1999, and accepted in revised form December 6, 2000.The lipid mediator prostaglandin E2 (PGE 2 ) has diverse biological activity in a variety of tissues. Four different receptor subtypes (EP1-4) mediate these wide-ranging effects. The EP-receptor subtypes differ in tissue distribution, ligand-binding affinity, and coupling to intracellular signaling pathways. To identify the physiological roles for one of these receptors, the EP1 receptor, we generated EP1-deficient (EP1 -/-) mice using homologous recombination in embryonic stem cells derived from the DBA/1lacJ strain of mice. The EP1 -/-mice are healthy and fertile, without any overt physical defects. However, their pain-sensitivity responses, tested in two acute prostaglandin-dependent models, were reduced by approximately ...

Spinal inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype

“…Other, EP2 receptorindependent mechanisms of inflammatory hyperalgesia appear to be of major relevance only early in the development of inflammation and are most likely peripheral in nature. They probably include the activation of EP1 or prostacyclin (IP) receptors, as demonstrated by the deficits in peripheral inflammatory pain sensitization observed in EP1 receptor-or IP receptor-deficient mice (8,10). It is apparent from our study that neither EP2 nor EP3 receptors contribute to paw swelling or peripheral thermal sensitization.…”

“…These receptors differ in their tissue distribution, signaling pathways, and physiological functions, which should allow the treatment of inflammatory pain with much greater specificity than currently achievable by the global blockade of PG synthesis via COX inhibitors. Studies performed either in mutant mice lacking individual PG receptors (8)(9)(10) or with synthetic PG receptor ligands (e.g., refs. 11, 12) have not yet provided a coherent picture of which EP receptors are responsible for inflammatory pain sensitization.…”

Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist

“…PGE2 has both vasodilating and vasoconstricting properties, and EP1 and EP3 may mediate the vasoconstricting action (25,26). Treatment of rats with ONO-8713 resulted in transient and slight reduction in BP at 4 wk as compared with untreated or aspirin-treated rats (P Ͻ 0.05; Table 1).…”

CJ-023,423 (Grapiprant) a Potential Novel Active Compound with Antihyperalgetic Properties for Veterinary Patients

“…EP1 is coupled to intracellular Ca 2+ mobilization, EP2 and EP4 are coupled to stimulation of adenylate cyclase via Gs protein and EP3 is coupled to inhibition of adenylate cyclase via Gi protein. Studies performed either in mutant mice lacking the individual PG receptors (Stock et al, 2001) or with synthetic EP receptor agonist/antagonist (Nakayama et al, 2002) have not yet provided a coherent picture of which EP receptors are responsible for inflammatory pain. Recently it has been reported that EP4 knockdown with intrathecally delivered short hairpin RNA attenuates inflammation-induced thermal and mechanical behavioral hypersensitivity (Lin et al, 2006), suggesting that EP4 is a potential target for the pharmacological treatment of inflammatory pain.…”