Characteristics and consequences of subcellular calcium signalling in spinal neurons and glia in chronic inflammatory and neuropathic pain


Activity-induced changes in intracellular Ca2+ levels ([Ca2+]i) play an invaluable role in processes that control persistent adaptations within the central nervous system (CNS). Indeed, Ca2+ signaling in spinal cord neurons, astrocytes, and microglia is strongly implicated in maladaptive pain plasticity. While it is well accepted that the spatiotemporal characteristics of a given [Ca2+]i rise determine cellular responses, surprisingly little is known about the features of synaptic activity-triggered Ca2+ signals in distinct subcellular compartments within spinal neuroglial networks, whether and how they are altered in chronic pain, and how they contribute to the cellular plasticity underlying pain hypersensitivity. We hypothesize that Ca2+ represents a key trigger for the long-lasting functional changes in cellular excitability and activity that underlie persistent pain sensitivity, and that altered cellular responsiveness following an acute painful insult may contribute to pain chronicity in a feed-forward manner via concomitant changes in sensory afferent activity-evoked Ca2+ transients.

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Reciprocal neuroglial interactions involving the activity
of excitatory and inhibitory neurons, astrocytes, and microglia are critically
involved in CNS plasticity, including in learning and memory,
fine motor control, and neurodegenerative disease.
A major mediator of these interactions is Ca2+.
In this study, we are characterizing subcellular Ca2+ signaling
in identified cells within spinal neuroglial networks,
and investigating the role of nuclear Ca2+ signaling in
spinal neurons and glia in the development and maintenance of
chronic pain and pain-associated morphological plasticity.

We further propose that nuclear Ca2+ signaling in spinal neurons and glia triggers functional and morphological plastic changes in these cells that are propagated throughout the entire spinal neuroglial network to ultimately result in the generation and maintenance of a persistent pain phenotype. To address these hypotheses, the proposed study will first provide a comprehensive analysis of the cellular and subcellular Ca2+ activation circuitry of spinal neurons and glia in naïve and persistent pain states and will, in a second set of experiments, reveal whether nuclear Ca2+ signaling in defined cell types triggers the morphological changes involved in central sensitization and ultimately resulting in chronic pain hypersensitivity. Our study involves in vivo manipulations of neurons and glia in the mouse spinal cord dorsal horn, cellular functional and morphological assessments in inflammatory and neuropathic pain models, and characterization of nociceptive sensitization.

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