Chronic pruritus occurs frequently in hepatobiliary diseases, is hard to control pharmacologically, and can seriously reduce the quality of life. The levels of lysophosphatidic acid (LPA) and its forming enzyme autotaxin were increased in the serum of cholestatic patients with pruritus compared to those without pruritus and correlated with itch severity and response to treatment (Kremer, 2010). We were able to determine by using microfluometry, that LPA 18:1 elevates cytosolic free calcium concentrations in cell cultures from sensory ganglia of C75BL/6 mice. Only 1.6% of the cells activated by LPA18:1 were identified as neurons, the majority were satellite glial cells. An inverse correlation between the LPA-response and the calcium responses to potassium and signature TRP channel agonists could be shown. The involvement of TRP channels was further tested by using transfected HEK293t cells which indicated, that LPA only marginally activates TRPV1/TRPA1. The responses to LPA in glia cells of TRPV1 and TRPA1 knockout mice were not reduced compared to cells from wild type mice. LPA desensitized responses to subsequent stimulation with other pruritogens. Pharmacological assays as well as mRNA levels concordantly suggest the observed responses are mediated by LPA receptor 1. LPA-induced intracellular calcium responses were almost identical in absence or presence of extracellular calcium, but could be depleted by thapsigargin, suggesting a calcium release from the endoplasmic reticulum as downstream signalling. In summary, LPA18:1 is a likely pruritogene in cholestatic pruritus which activates glial cells. This can lead to an altered neuronal function, which poses the question of a glial component in the regulation or even the generation of cholestatic itch.