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Papers of the Week

Papers: 17 Jun 2023 - 23 Jun 2023

Basic Science

Animal Studies, Molecular/Cellular

Neuropathic Pain

2023 Jun 09



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


Prokhorenko MA, Smyth JT


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 Ca signaling mechanisms. Clear definition of the astrocyte Ca 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. Ca release from astrocyte endoplasmic reticulum (ER) Ca stores via the inositol 1,4,5-trisphosphate receptor (IP R) is required for centrally mediated neuropathic pain (Kim et al, 2016); however recent evidence suggests the involvement of additional astrocyte Ca signaling mechanisms. We therefore investigated the role of astrocyte store-operated Ca entry (SOCE), which mediates Ca influx in response to ER Ca store depletion. Using an adult 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 Ca signaling events three to four days following nerve injury. Astrocyte-specific suppression of Stim and Orai, the key mediators of SOCE Ca 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 , adding key new understanding to the astrocyte Ca signaling mechanisms involved in chronic pain.