UC San Diego

Neuropathic pain is a chonic pain state caused by lesions or diseases in the nervous system. Unlike acute pain, neuropathic pain persists without obvious injury or stimuli and can severely interfere with normal daily life for those who suffer from it. Despite numerous efforts on studying its mechanism and possible treatments, there is no effective treatment currently available to remove or alleviate this symptom. This dissertation aims to provide further understanding into the relationship between lysophosphatidic acid (LPA) signaling and neuropathic pain development. LPA is one of the lysophospholipids that has wide range of signaling abilities through its G protein- coupled receptors, LPA₁ to LPA₆. LPA is involved in multiple systems in both normal and pathological conditions, such as development, cardiovascular function, the reproductive system, cancer, and neuropsychiatric diseases. The first evidence of LPA involvement in neuropathic pain was shown in LPA₁ deficient animals where injury-induced neuropathic pain is prevented. Here we demonstrate for the first time, that a second LPA receptor, LPA₅, is also involved in neuropathic pain through pCREB activation in the spinal dorsal horn neurons via a mechanism, which is distinct from LPA₁. This suggests an alternative LPA signaling pathway in neuropathic pain development and LPA₅ could serve as potential therapeutic target. We also analyzed the effect of LPA on Schwann cell physiology, since LPA₁ deficient mice also showed decreased demyelination in response to nerve injury. With LPA₁ null mice, we demonstrated that LPA₁ signaling is important for proper myelination during development and also regulates Schwann migration along dorsal root ganglion (DRG) neurons. These data suggest an important regulatory role of LPA on Schwann cell biology. Furthermore, we have shown that sphingosine 1-phosphate (S1P), another lysophospholipid closely related to LPA, is also involved in Schwann cell biology and can modify LPA signaling. Through the balance between S1P₂ and S1P₃, S1P can fine-tune LPA₁ signaling in both Schwann cell migration and myelination gene regulation. Through these studies, we have extended our understanding of LPA signaling in neuropathic pain and Schwann cell biology. Hopefully these findings will bring us a step closer to potential therapeutic treatments