Astrocyte Calcium Signaling in Chronic Pain. - SUMMARY Acute nerve injuries often lead to chronic pain. Chronic pain is a common condition that can have devastating impacts on quality of life and there are currently few non-addictive drugs available that effectively treat chronic pain. Better understanding of how acute injury results in chronic pain is essential to the development of new pain medications. Chronic pain involves central sensitization, whereby pain networks in the central nervous system become hypersensitized. During central sensitization astrocytes can be activated by excitatory neurotransmitters, and activated astrocytes then release cytokines and other factors that are required for pain network sensitization. These astrocyte functions are regulated by complex Ca2+ signaling mechanisms. The long-term goals of our research are to define the specific Ca2+ signaling mechanisms required in astrocytes for chronic pain, because defining these mechanisms may reveal new therapeutic targets for pain intervention. We address this using powerful genetic tools in a Drosophila model of chronic pain. Our recent work demonstrates that highly conserved store-operated calcium entry (SOCE) channels are required in astrocytes for the transition from nerve injury to chronic pain. SOCE channels are activated when endoplasmic reticulum (ER) Ca2+ stores are depleted and they are an essential component of many Gq-coupled neurotransmitter receptor signaling mechanisms. SOCE channels are notable for their ability to specifically activate cytokine and other gene expression through activation of the calcineurin/NFAT signaling pathway. Thus, SOCE channels may form a vital link between nerve injury-induced astrocyte activation and astrocyte release of neuroactive cytokines. The specific goals of this proposal are to determine how nerve injury results in the activation of astrocyte SOCE and to determine the role of SOCE in activating calcineurin/NFAT – mediated neuroinflammatory signaling required for chronic pain. We will address this by 1) assessing astrocyte Gq-coupled receptor signaling in injury-induced SOCE activation; 2) testing the ability of SOCE to drive astrocyte cytokine expression through calcineurin/NFAT activation; and 3) defining the role of gap junctions in inter-astrocyte propagation of injury-induced Ca2+ signals. The results of this work will bring clearer understanding of the astrocyte Ca2+ signaling mechanisms involved in pain chronification and may lead to the development of desperately needed non-opioid pain therapeutics.
