Our present results support a
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.
Introduction Accumulating evidence linking stroke and Alzheimer\'s disease (AD) indicates that each exacerbates the severity of the other (Jendroska et al., 1995, Koistinaho and Koistinaho, 2005). Because there are few effective treatments for AD, especially when stroke supervenes in these patients, finding a common pathway that exacerbates neuronal loss and get married damage might provide a potential therapeutic target. Over the years, prostaglandin E2 (PGE2) and cyclooxygenase (COX)-2, the rate-limiting enzyme responsible for prostaglandin production, have become largely discussed targets for exploration in therapy for AD and stroke patients (Ahmad et al., 2008, Bazan et al., 2002, Santovito et al., 2009). Clinical use of nonsteroidal anti-inflammatory drugs or selective COX inhibitors is associated with various concerning side effects (Donnelly and Hawkey, 1997, Ray et al., 2004); thus, studying the downstream pathway may provide a unique therapeutic target which would allow more selectivity by targeting one prostaglandin (i.e., PGE2) and one receptor simultaneously, not simply inhibiting synthesis of all prostaglandins. Previously, the EP1 receptor expression in central nervous system (CNS) neurons has been documented in the literature; for example, signals for EP1 receptor mRNA have been exposed in C57BL/6 mouse brain, e.g., www.brain-map.org, and the EP1 receptor has also been documented by various independent teams at the protein level in the central nervous system and on neuronal cells (Carlson et al., 2009, Kawano et al., 2006). Additionally, previous studies by others and by us have provided physiological evidence that deletion of EP1 receptor significantly attenuates focal ischemic and excitotoxic brain damage and that treatment with selective receptor ligands provided significant anatomical and functional biological outcomes (Ahmad et al., 2006, Kawano et al., 2006). Thus, our study focuses on delineating the role of PGE2 EP1 receptor in an AD model in the setting of cerebral ischemia. Based on this team effort, we propose that the EP1 receptor may be critical in the inflammatory and cell death pathways that are both hallmarks in the neurodegenerative conditions of AD and stroke. We used the APPswe/PS1ΔE9 double gene mutation (APP/PS1) AD mouse model and crossed them with EP1 gene knockout (EP1−/−) mice, and explored the potential EP1 receptor role in stroke and AD-like conditions. We compared β-amyloid (Aβ) plaques, Aβ40 and Aβ42 levels, and behavioral outcomes of ischemia in APP/PS1xEP1−/− and APP/PS1 mice together with their non-AD control mice. Furthermore, to explore the potential mechanism of the neuroprotective effect of genetic knocking out the EP1 receptor, we investigated intracellular Ca2+ response in an Aβ-enriched environment in cultured neurons.