Uncovering astrocyte contributions to neuropathic pain

Project Summary Chronic pain poses a significant societal burden, affecting over 50 million Americans. New cases of chronic pain occur more frequently in the U.S. than diabetes, depression, or high blood pressure. Approximately 20 percent of chronic pain patients experience neuropathic pain due to nervous system injury or disease. Current neuropathic pain management relies on repurposed drugs with uncertain efficacy and known side effects, necessitating safer and more effective pharmacologic and non-pharmacologic approaches. However, existing knowledge gaps in basic research have hindered the development of more effective treatments. Understanding the mechanisms underlying neuropathic pain and how interventions interact with these mechanisms is imperative. The spinal cord plays a crucial role in neuropathic pain; however, technical limitations of traditional research approaches have left the mediators of this signaling incompletely understood. While significant attention has been directed toward neuronal cell types and circuits contributing to neuropathic pain, the contributions of non-neuronal cells are less understood. Astrocytes, glial cells of the central nervous system, cover all gray and white matter regions, allowing them to affect various aspects of neural circuit function, including neuronal excitability, synchrony, and synaptic plasticity. Accordingly, there is growing interest in better understanding astrocytes' role in neuropathic pain pathology. Nonetheless, the precise relationship between spinal astrocyte excitation and neuronal spiking, plasticity, or behavioral responses remains incompletely understood. Preliminary data in an established neuropathic pain model indicate that astrocyte-targeted interventions can abrogate mechanical and thermal hypersensitivity after nerve injury. Based on these findings, it is hypothesized that peripheral nerve injury disrupts neuron-astrocyte communication, promoting abnormal neural circuit activity and plasticity, and regulating astrocyte function can mitigate neural circuit dysfunction and pain behavior. This project aims to 1) determine in detail how peripheral nerve injury alters dorsal horn astrocyte function, 2) elucidate how targeted interventions control dorsal horn astrocyte function after nerve injury, and 3) characterize how targeted modulation of astrocyte function controls abnormal neuronal activity, connectivity, and pain behavior following nerve injury. Ultimately, this work will yield new insights into the manifestation of neuropathic pain at synaptic, cellular, and circuit levels, providing crucial information for the development of more effective pharmacologic or non-pharmacologic interventions in the future.