Chronic pain affects over 100 million adults in the United States and is considered exceptionally difficult to treat. One of the primary reasons that individuals visit the clinic is due to pain as a primary factor or arising secondarily to another disease or disorder. The etiology of pathological pain conditions have not been fully elucidated due to its complexity. This project investigates the role of glycogen synthase kinase 3 beta (GSK-3), adenosine monophosphate-activated protein kinase (AMPK), and lanthionine synthetase C-like 2 protein (LANCL2) in regulating inflammation of the central nervous system (CNS) and pathological pain. Tissue and nerve injury produce inflammation, which is a critical component contributing to the development and maintenance of pathological pain conditions. The accumulation of inflammatory cells at the peripheral injury site, proliferation and activation of microglia and astrocytes in the spinal dorsal horn of the spinal cord, as well as the production of pro-inflammatory cytokines and mediators at the injury site and the spinal dorsal horn have all been shown to contribute to the genesis of pathological pain. Targeting signaling pathways regulating these processes may prove effective in developing analgesics to treat pain.This work provides compelling evidence through reviewing the literature and published results that GSK-3 is a novel target in the spinal cord to treat pain behaviors. We further show through published or submitted results that the activity of AMPK modulates neuroinflammation and pathological pain, in part through GSK-3 activity and aberrant reactive oxygen species in the spinal cord. Next, we provide results that a newly identified protein in the spinal cord, LANCL2, can mediate neuroinflammation and nociceptive behaviors. Lastly, we describe how these findings influence the field for researchers, clinicians, and ultimately patients.