Sphingosine 1-phosphate induced ionic currents in nociceptors and acute pain

Acute pain regularly results as a consequence of surgical interventions, when the surgeon induces tissue injury and damage to blood vessels, vascular leakage, accumulation and activation of thrombocytes and plasma extravasation. Human platelets contain high concentrations of sphingolipids in particular sphingosine 1-phosphate (S1P) which is actively released upon platelet activation and micromolar S1P concentrations are measured in blood plasma. Experimental injection of plasma induces pain, and experimentally activated thrombocytes excite nociceptors. We therefore propose S1P as a novel key mediator of acute nociceptor excitation and pain. We use an interdisciplinary approach to investigate the mechanism by which S1P acts on pain-sensing neurons, the nociceptors. It is of importance to characterise ionic conductances activated by S1P (IS1P) in sensory neurons and to address the receptor/cellular signalling mechanism required for IS1P activation. We investigate chloride conductances in sensory neurons activated by S1P, and siRNA gene silencing strategies will be used to identify candidate genes for chloride channels activated by S1P in neuroblastoma cells and nociceptors. The role of S1P and chloride channels in acute post-operative pain will be addressed. Although post-operative pain represents a major clinical problem and severely affects the patients` recovery, pain relief strategies so far are restricted to the classical opioids or non-opioidergic analgesics. We expect to obtain new mechanistic insight into the importance of S1P for acute traumatic and post-operative pain which provide the basis for the development of novel analgesic strategies.

Acute pain regularly results as a consequence of surgical interventions, when the surgeon induces tissue injury and damage to blood vessels, vascular leakage, accumulation and activation of thrombocytes and plasma extravasation. Human platelets contain high concentrations of sphingolipids in particular sphingosine 1-phosphate (S1P) which is actively released upon platelet activation and micromolar S1P concentrations are measured in blood plasma. Experimental injection of plasma induces pain, and experimentally activated thrombocytes excite nociceptors. We therefore assessed S1P as a novel key mediator of acute nociceptor excitation and pain. We used an interdisciplinary approach to investigate the mechanism by which S1P acts on pain-sensing neurons, the nociceptors. We characterised ionic conductances activated by S1P (IS1P) in sensory neurons and addressed the receptor/cellular signalling mechanism required for IS1P activation. We investigated chloride conductances in sensory neurons activated by S1P, and siRNA gene silencing strategies was used to identify candidate genes CLCN3 andCLCN5 for chloride channels activated by S1P in neuroblastoma cells and nociceptors. The role of S1P and chloride channels in acute postoperative pain was addressed. Although post-operative pain represents a major clinical problem and severely affects the patients` recovery, pain relief strategies so far are restricted to the classical opioids or non- opioidergic analgesics. We obtained new mechanistic insight into the importance of S1P for acute traumatic and post-operative pain which provide the basis for the development of novel analgesic strategies.