Chronic pain mismanagement has led to opioid overuse, overdose related deaths and cardiovascular, renal and neurological complications at epidemic proportions. To combat these problems, it is essential to elucidate critical gaps in knowledge pertaining to the underlying mechanisms controlling the processes of initiation and maintenance of chronic pain conditions. The current paradigm implies that tissue or nerve damage triggers protective immune response that should be resolved as soon as its function is fulfilled. If inflammation is not resolved, then transition from the acute to chronic pain could occur. We propose that critical regulators of a delicate balance between protective immunity and immunopathology could be good candidates for controlling a sustained inflammatory response after tissue or nerve damage; and subsequently, regulating the process of development of chronic pain. One of such critical regulators is lymphotoxin-beta receptor (LTβR), a member of the tumor necrosis factor receptor family. The objective of this proposal is to elucidate whether and how peripheral LTβR signaling regulates the process of the initiation and maintenance of pain in inflammatory and chemotherapy-induced peripheral neuropathy (CIPN) models. Based on the existing literature and our preliminary data, we propose an entirely novel regulatory mechanism for the initiation and maintenance of inflammatory as well as CIPN pain wherein peripheral LTβR signaling controls these processes by regulating the network of transcriptional and cellular plasticity in hindpaw and DRG cells. Accordingly, our central hypothesis is that peripheral LTβR signaling controls the processes of initiation and maintenance of inflammatory and CIPN pain via governing the network of transcriptional and cellular plasticity mediating communication between peripheral cells and sensory neurons. Our hypothesis will be tested by three interconnected yet independent aims. Aim 1 defines the impact of peripheral LTβR signaling on the initiation and maintenance of inflammatory and CIPN pain in male and female mice. Aim 2 determines the cellular basis of LTβR signaling at the periphery during inflammatory and CIPN pain. Aim 3 examines the impact of peripheral LTβR signaling on inflammation- and CIPN-induced sensory neuronal and non-neuronal transcriptional and cell plasticity in paw and DRG. The proposed study is innovative because it describes conceptually novel peripheral regulatory mechanism controlling the processes of initiation and maintenance of chronic pain, which are regulated by LTβR. The proposed research is significant as it (1) advances our understanding of mechanisms regulating the transition from acute to chronic pain; and (2) offers LTβR signaling antagonists as potential therapeutic targets for prevention and full and sustained reversal of CIPN chronic pain, as well as effective and long-lasting management of inflammatory pain.