Lanthionine Synthetase C‐like Protein 2: A potential therapeutic target for treating neuropathic pain

Abstract

Glial activation and over‐production of pro‐inflammatory cytokines and chemokines in the spinal cord are critical mechanisms underlying the genesis of neuropathic pain. While pro‐inflammatory signaling molecules have been extensively investigated, much less is known about anti‐inflammatory signaling pathways and systems. Studies in recent years have demonstrated that lanthionine synthetase C‐like 2 protein (LANCL2) is expressed in cells related to the immune function, like T cells, macrophages, endothelial and epithelial cells, and dendritic cells, suggesting its potential as a target for immunoregulation. In this study, we determined the role of LANCL2 in the genesis of neuropathic pain. Specifically, we show that LANCL2 protein is expressed in spinal dorsal horn and down‐regulated in rats with neuropathic pain. Knockdown of spinal LANCL2 induces mechanical allodynia and thermal hyperalgesia, which is concomitantly accompanied with increases in extracellular signal‐regulated kinase (ERK) activity, tumor necrosis factor alpha (TNF‐α) production, and the activation of astrocytes and microglia in the spinal dorsal horn. Activation of spinal LANCL2 by intrathecal administration of abscisic acid alleviates mechanical and thermal hypersensitivity induced by nerve injury. Pre‐emptive pharmacological activation of LANCL2 prevents the down‐regulation of LANCL2 protein expression, and significantly attenuates the development of mechanical allodynia and thermal hyperalgesia in rats induced by nerve injury. These behavioral changes were accompanied with the suppression of ERK activity and TNF‐α production, and astrocyte and microglia activation in the spinal dorsal horn of rats with nerve injury. Our study provides evidence that LANCL2 may be a potential molecular target for the development of analgesics for neuropathic pain and the management of a wide range of conditions involving neuroinflammation.Support or Funding InformationNS064289; NS107569