Chronic pain is a hallmark of many disease conditions, including nerve and spinal cord injury. Current mainstays of pain management include analgesics and anesthetics, treatments that are used despite their uncertain efficacy and known side effects. Safer and more productive approaches for pain management are urgently needed, but knowledge gaps in basic research have hampered the development and translation of novel treatments. To accelerate this process an improved understanding of the cellular and molecular basis of pain signaling is required. The spinal cord is a crucial signaling hub involved in communicating pain-related signals between peripheral organs and the brain. As the first site of sensory integration within the central nervous system (CNS), it plays essential roles in central sensitization. Much attention has focused on the neuronal cell types and circuits that contribute to this process. However, considerably less is known about the contributions of non-neuronal cells, such as astrocytes. While morphological changes in spinal astrocytes in relation to onset and progression of chronic pain have been well characterized, little is known about their dynamic activity patterns and how they relate to neuronal spiking or sex-specific immune responses. Historically, technical challenges have prevented such measurements in preclinical animal models under naturalistic conditions. The recent development of two-photon and miniaturized one-photon imaging approaches has enabled real-time measurement of cellular calcium activity in behaving mammals. This has provided first insights into how sensory information from mechanoreceptors and nociceptors in the skin acutely activates dorsal horn neurons and astrocytes. Using these cutting-edge imaging approaches in combination with computational, genetic, and behavioral techniques, the objective of this proposal is to define how astrocyte calcium activity changes in relation to neuropathic pain onset and progression, how its targeted manipulation influences neuronal and non-neuronal responses, and how it alters molecular signaling and animal behavior. The rationale for the proposed research is that by uncovering cellular and molecular mechanisms that contribute to pain onset or progression, new analgesic interventions can be devised.
Three specific aims will be pursued: 1) Determine how astrocyte calcium excitation relates to neuropathic pain under naturalistic conditions; 2) Determine how inhibition of astrocyte calcium excitation modulates normal and aberrant sensory processing, and 3) Determine molecular pathways involved in astrocyte calcium excitation-mediated modulation of normal and aberrant sensory processing. In summary, this work will uncover how changes in astrocyte activity contribute to neuropathic pain on molecular, cellular, and behavioral levels. It will extend current models of how non-neuronal cells contribute to persistent pain specifically and CNS function broadly.
Experiments proposed here will provide new knowledge about the mechanisms that underlie pain signaling in the central nervous system, particularly the spinal cord. This knowledge will help accelerate the rational design of new or more effective treatments for pain disorders, such as nerve or spinal cord injury.
