Finally by injecting zymosan A into

Finally, by injecting zymosan A into the hindpaw the contribution of EP1 to pain sensitization was studied in a model that resembles a more complex natural inflammation (). This was particularly important as the expression of EP receptors might change during inflammation. In wild-type mice, zymosan A caused local paw swelling and led to strong mechanical and thermal sensitization. EP1 mice showed virtually identically responses throughout the time course of the experiment. Because at the dose employed, zymosan A-induced pain sensitization is mainly due to sensitization induced by spinally produced PGE , the absence of a phenotype in this test is consistent with only a minor contribution of EP1 receptors to spinal pain sensitization. Among the four PGE receptors, the EP1 subtype has been proposed as one of the most promising targets against inflammatory hyperalgesia. Early work showed that EP1 mice exhibited significantly reduced nocifensive responses to intraperitoneal injection of acetic Oseltamivir acid and to 2-phenyl-1,4-benzoquinone (PBQ) , and a tendency to reduced responses in the formalin test , . Subsequent development of EP1 receptor antagonists proved analgesic activity in a variety of pain models. One of the first specific EP1 receptor antagonists that became available was ONO-8711. This compound reduced mechanical hyperalgesia in nerve injured rats after systemic administration , in rats after intrathecal injection, in the carrageenan model , in an incision model of postoperative pain , or when intrathecally co-injected together with PGE . The more specific ONO-8713 has been reported to reverse thermal hyperalgesia in mice when co-injected peripherally together with PGE . However, further data on ONO-8713 in other pain models is not available. Other EP1 receptor antagonists more recently developed by GlaxoSmithKline showed analgesic activity after systemic administration in a sub-chronic model of knee joint arthritis , . Although these studies provide significant evidence for an analgesic action of EP1 receptor antagonists, a systematic analysis of the contribution of peripheral versus central sites and on the relevance of EP1 receptors for heat and mechanical sensitization is largely lacking. This may still be clinically relevant as a significant contribution of central EP1 receptors would prompt for antagonists being able to cross the blood brain barrier, and because chronic pain patients appear to suffer more from mechanical hypersensitivity than from heat hyperalgesia. Our present results support a major role of EP1 receptors in peripheral heat sensitization and a smaller contribution to central heat sensitization but no contribution to mechanical sensitization. While the contribution of peripheral EP1 receptors to heat hyperalgesia is in good agreement with the antagonist study by Moriyama et al. , its role in mechanical and spinal sensitization is more controversial and the exact reasons for the discrepant findings are difficult to determine. Possible explanations include species differences (mice versus rats), compensatory up-regulations of other EP receptors in the gene deficient mice, and off-target effects of antagonists. The latter may be particularly relevant when antagonists are injected locally, in this case intrathecally, at concentrations which exceed the Ki values at the EP1 receptor by several orders of magnitude. Reduced hyperalgesic responses to intrathecally or subcutaneously injected PGE in EP2 receptor deficient mice reported in the present study and in previous studies , (for a review see ) clearly indicate that EP receptors different from EP1 are also involved in pain sensitization.