Astrocytes comprise the major glial cell type in the brain and regulate numerous brain functions including neural development, clearance of neurotransmitters, and regulation of blood flow. Recent evidence indicates that astrocytes also play important roles in regulating neuronal excitability and synaptic transmission by secreting a variety of neuroactive factors including proinflammatory cytokines. These cytokines evoke a vast array of changes in neuronal and glial function including alterations in Ca2+ signaling and synaptic transmission, which implicated in pathologies such as neuropathic pain. In particular, following nerve injury, inflammatory cytokines including TNFα, IL1β , and IL-6 are rapidly produced by glial cells to enhance the strength of excitatory synaptic transmission in nociceptive circuits in the spinal cord and induce chronic pain. While microglia, a macrophage-like cell type in the brain have received the lion's share of the attention in this process, the role of astrocytes and the cellular checkpoints that regulate this process are less well understood. Our preliminary findings indicate that store-operated Ca2+ release-activated Ca2+ (CRAC) channels are a major mechanism for purinergic-evoked Ca2+ signals in astrocytes and their activation in spinal astrocytes strongly stimulates the transcription and secretion of a wide range of proinflammatory cytokines and chemokines. Based on this evidence, we hypothesize that CRAC channels are essential regulators of astrocyte-mediated neuroinflammation in neuropathic pain. We propose three specific aims to address this hypothesis: 1) Define the role of CRAC channels for agonist-evoked Ca2+ elevations and the inflammatory output of astrocytes, 2) Determine the contributions of CRAC channel-mediated inflammatory cytokines for the maladaptive potentiation of synaptic transmission in the dorsal horn of the spinal cord following nerve injury, and 3) examine the in vivo relevance of CRAC channel-mediated inflammatory cytokine production from astrocytes for neuropathic pain. We will approach these questions using genetic knockouts of CRAC channel proteins in astrocytes, biochemical and transcriptome analysis of cytokine synthesis, slice electrophysiology, Ca2+ imaging, and behavioral analysis. Results from these studies will advance our understanding of the physiological role of CRAC channels for regulating astrocyte-mediated neuroinflammation and aid the quest for developing new astrocyte-targeted therapies for pathological diseases affecting brain function.