Lymphotoxin-beta receptor controls the development of chronic pain

Preventing the development of chronic pain is crucial to avoiding difficult-to-manage, debilitating pain conditions. Our research identifies the lymphotoxin beta receptor (LTβR) as a peripheral master regulator in this process. Activation of LTβR induces mechanical allodynia and increases sensory neuron excitability by engaging peripheral non-neuronal cells, including macrophages and stromal cells. Conversely, local blockade of LTβR reduces neuronal hyperexcitability and irreversibly prevents chronic pain in a neuropathic preclinical model. These LTβR effects are driven by both LTβ and LIGHT. Transcriptomic analysis reveals that LTβR regulates the development of chronic pain by coordinating a peripheral gene-plasticity network that involves immune-related genes and diverse cell types. Overall, LTβR acts as a master regulator controlling the development of pain chronicity by shaping a peripheral gene plasticity network that drives sensory neuronal sensitization.