Inflammation can augment dramatically the sensitivity of nociceptive sensory neurons. In some cases, the actions of inflammatory mediators are fairly well understood;however, there are signalling pathways for which we have very little knowledge. Such a pathway is the one in which the activating ligand is sphingosine 1- phosphate (S1P). Upon activation, S1P is released from a variety of immuno-competent cells and appears to play an important role in their chemotaxis and migration. S1 P is the endogenous ligand for a family of G protein-coupled receptors originally named EDG receptors (endothelial differentiation gene) and are now known as the S1 P receptor family (S1 PRJ. Our understanding of the role of S1 P in the onset and regulation of the inflammatory response is very limited, even in model systems. In our work on NGF, we discovered that externally applied S1 P significantly increased neuronal excitability and that these neurons expressed the mRNA for S1 PRs. Because of the emerging importance of S1 P in the onset of inflammation, this raises the question whether S1 P is an important primary messenger communicating between inflammatory cells and sensory neurons. To answer this question, three SAs are proposed: SA1 will establish which S1 PRs are expressed in sensory neurons and whether these receptors co-localize with specific defined populations of sensory neurons. SA2 will determine, using patch-clamp recording, which specific membrane currents are modulated by S1 P and how these changes lead to enhanced neuronal firing. S1 PRs involved in this sensitization will be determined by single-cell RT-PCR analysis and siRNA to knock-down the expression of specific receptors. SA3 in collaboration with Dr. Jun-Ming Zhang, will determine the capacity of S1 P to affect nociceptive behaviors in rats wherein S1 P is perfused directly onto the L5 DRG. Results from such studies will provide an important understanding of the potential communication between the immune and neuronal systems and lead to interventions that reduce the enhanced pain associated with inflammation.
This project will examine the mechanisms whereby a novel Iysophospholipid, sphingosine 1-phosphate, increases the ability of sensory nerves to respond to painful stimulation. Sphingosine 1-phosphate binds to receptors on the neuronal membrane and activates biochemical pathways inside the neuron that ultimately control the activity of ion channels that produce the action potential. Additional experiments will be performed in whole animals to determine the effects of sphingosine 1-phosphate on how the animal's response to noxious stimulation is altered. The role of sphingosine 1-phosphate in the onset and maintenance of the inflammatory response is just beginning to be understood. Therefore, results from such studies will provide an important understanding of the potential communication between the immune and neuronal systems and lead to interventions that reduce the enhanced pain associated with inflammation.
| Kays, J S; Li, Chao; Nicol, G D (2012) Expression of sphingosine 1-phosphate receptors in the rat dorsal root ganglia and defined single isolated sensory neurons. Physiol Genomics 44:889-901 |
| Li, Chao; Chi, Xian Xuan; Xie, Wenrui et al. (2012) Sphingosine 1-phosphate receptor 2 antagonist JTE-013 increases the excitability of sensory neurons independently of the receptor. J Neurophysiol 108:1473-83 |
| Xie, Wenrui; Strong, Judith A; Kays, Joanne et al. (2012) Knockdown of the sphingosine-1-phosphate receptor S1PR1 reduces pain behaviors induced by local inflammation of the rat sensory ganglion. Neurosci Lett 515:61-5 |
| Chi, Xian Xuan; Nicol, G D (2010) The sphingosine 1-phosphate receptor, S1PR?, plays a prominent but not exclusive role in enhancing the excitability of sensory neurons. J Neurophysiol 104:2741-8 |
