Lancl2: A Potential Target For The Treatment Of Neuropathic Pain

Abstract

ABSTRACT

LANCL2: A POTENTIAL TARGET FOR THE TREATMENT OF NEUROPATHIC PAIN By: DAVID JAMES CHRISTY Under the direction of DR. HAN-RONG WENG, Ph.D, M.D.

Dysfunctional pain signaling is a hindrance to a normally functioning organism. Neuropathic pain is caused by damage or dysfunction of the nervous system, such as a pinched nerve, diabetic neuropathy, cancer, and chemotherapy treatments. Current drugs used for treatment of neuropathic pain are either not safe or effective. Discerning signaling molecules regulating neuropathic pain in animal models can offer molecular targets for the development of novel analgesics. Neuroinflammation in the spinal dorsal horn is a crucial mechanism underlying the genesis of neuropathic pain. Given that LANCL2, a membrane associated protein, is engaged in regulation of inflammation, the purpose of this study was to determine whether LANCL2 has pro- or antinociceptive effects in the spinal dorsal horn. We analyzed levels of pro-inflammatory cytokines as well as LANCL2 to determine the role of spinal LANCL2 in the genesis of neuropathic pain. Neuropathic rats induced by partial sciatic nerve ligation were used. Specifically, we found that protein expression of LANCL2 in the spinal dorsal horn was reduced in neuropathic rats 10-days after the nerve injury in comparison with sham operated animals. This was accompanied with activation of microglia and astrocytes, increased levels of ERK, TNF-α, and IL-1ß at the same site. Meanwhile, the spinal dorsal horn of neuropathic rats had lower levels of abscisic acid, an endogenous ligand of LANCL2. Furthermore, intrathecal application of abscisic acid suppressed mechanical and thermal hypersensitivity in neuropathic rats. Immunostaining experiments demonstrated that LANCL2 is expressed in neurons but not astrocytes; the data from microglial staining was inconclusive. Our study suggests that activation of LANCL2 signaling pathway in the spinal cord is a powerful approach to conquer neuropathic pain.