Sphingosine-1-phosphate (S1P) is released by immune cells and is thought to play a key role in the onset of the inflammatory response. The question remains whether this lipid mediator also contributes to the enhanced sensitivity of nociceptive neurons that is associated with inflammation. Therefore, we examined whether S1P alters the excitability of small diameter, capsaicin-sensitive sensory neurons by measuring action potential (AP) firing and two membrane currents critical in regulating AP properties. External application of S1P augments the number of APs evoked by a depolarizing current ramp. Enhanced firing is associated with a decrease in rheobase and an increase in resistance at firing threshold although neither firing threshold nor resting membrane potential are changed. S1P enhanced the tetrodotoxin-resistant sodium current (TTX-R I_Na) and decreased the total outward potassium current (I_K). When neurons were internally perfused with GDP--S, the S1P-induced increase in APs was completely blocked and suggest the excitatory actions of S1P are mediated through G protein-coupled receptors called EDG or S1PR. In contrast, internal perfusion with GDP--S and S1P increased the number of APs evoked by the current ramp. These results and our finding that the mRNAs for S1PRs are expressed in both intact DRG and cultures of adult sensory neurons supports the notion that S1P acts on S1PRs linked to G proteins. Together, these findings demonstrate that S1P can regulate the excitability of small diameter sensory neurons by acting as an external paracrine-type ligand through activation of G protein-coupled receptors and thus may contribute to the hypersensitivity during inflammation.