Inhibition of autotaxin activity ameliorates neuropathic pain derived from lumbar spinal canal stenosis

Abstract

Lumbar spinal canal stenosis (LSS) or mechanical compression of dorsal root ganglion (DRG) is one of the causes of low back pain and neuropathic pain (NP). Lysophosphatidic acid (LPA) is a potent bioactive lipid mediator that is produced mainly from lysophosphatidylcholine (LPC) via autotaxin (ATX) and is known to induce NP via LPA1 receptor signaling in mice. Recently, we demonstrated that LPC and LPA were higher in cerebrospinal fluid (CSF) of patients with LSS. Based on the possible potential efficacy of the ATX inhibitor for NP treatment, we used an NP model with compression of DRG (CD model) and investigated LPA dynamics and whether ATX inhibition could ameliorate NP symptoms, using an orally available ATX inhibitor (ONO-8430506) at a dose of 30 mg/kg. In CD model, we observed increased LPC and LPA levels in CSF, and decreased threshold of the pain which were ameliorated by oral administration of the ATX inhibitor with decreased microglia and astrocyte populations at the site of the spinal dorsal horn projecting from injured DRG. These results suggested possible efficacy of ATX inhibitor for the treatment of NP caused by spinal nerve root compression and involvement of the ATX-LPA axis in the mechanism of NP induction.