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bioRxiv · 10.1101/2023.06.08.544231

Astrocyte store-operated calcium entry is required for centrally mediated neuropathic pain

Prokhorenko, M. A.·Smyth, J. T.
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Abstract

Central sensitization is a critical step in chronic neuropathic pain formation following acute nerve injury. Central sensitization is defined by nociceptive and somatosensory circuitry changes in the spinal cord leading to dysfunction of antinociceptive gamma-aminobutyric acid (GABA)ergic cells (Li et al., 2019), amplification of ascending nociceptive signals, and hypersensitivity (Woolf, 2011). Astrocytes are key mediators of the neurocircuitry changes that underlie central sensitization and neuropathic pain, and astrocytes respond to and regulate neuronal function through complex Ca2+ signaling mechanisms. Clear definition of the astrocyte Ca2+ signaling mechanisms involved in central sensitization may lead to new therapeutic targets for treatment of chronic neuropathic pain, as well as enhance our understanding of the complex central nervous system (CNS) adaptions that occur following nerve injury. Ca2+ release from astrocyte endoplasmic reticulum (ER) Ca2+ stores via the inositol 1,4,5-trisphosphate receptor (IP3R) is required for centrally mediated neuropathic pain (Kim et al, 2016); however recent evidence suggests the involvement of additional astrocyte Ca2+ signaling mechanisms. We therefore investigated the role of astrocyte store-operated Ca2+ entry (SOCE), which mediates Ca2+ influx in response to ER Ca2+ store depletion. Using an adult Drosophila melanogaster model of central sensitization based on thermal allodynia in response to leg amputation nerve injury (Khuong et al., 2019), we show that astrocytes exhibit SOCE-dependent Ca2+ signaling events three to four days following nerve injury. Astrocyte-specific suppression of Stim and Orai, the key mediators of SOCE Ca2+ influx, completely inhibited the development of thermal allodynia seven days following injury, and also inhibited the loss of ventral nerve cord (VNC) GABAergic neurons that is required for central sensitization in flies. We lastly show that constitutive SOCE in astrocytes results in thermal allodynia even in the absence of nerve injury. Our results collectively demonstrate that astrocyte SOCE is necessary and sufficient for central sensitization and development of hypersensitivity in Drosophila, adding key new understanding to the astrocyte Ca2+ signaling mechanisms involved in chronic pain.

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Prokhorenko, M. A., Smyth, J. T.. 2023-06-09. Astrocyte store-operated calcium entry is required for centrally mediated neuropathic pain. https://doi.org/10.1101/2023.06.08.544231

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