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

Acute injuries transition to chronic neuropathic pain through central sensitization (CS), which involves plastic changes to nociceptive networks within the central nervous system. Astrocytes are essential mediators of CS, and many neuromodulatory functions of astrocytes are regulated by complex Ca²⁺ signaling mechanisms. The role of astrocyte Ca²⁺ signaling in CS and the specific astrocyte Ca²⁺ channels involved are poorly defined.

Our objective was to test the role of store-operated Ca²⁺ entry (SOCE), a highly conserved Ca²⁺ signaling mechanism that mediates Ca²⁺ influx in response to depletion of endoplasmic reticulum Ca²⁺ stores, in CS and neuropathic pain.

We used a Drosophila model of CS based on the development of thermal allodynia 7 days after acute nerve injury, combined with a transcriptional reporter of intracellular Ca²⁺ mobilization. In vivo, astrocyte-specific RNAi was then used to test the role of Orai SOCE channels and Orai-activating Stim proteins in injury-induced astrocyte Ca²⁺ signaling and thermal allodynia.

Astrocytes exhibited Stim and Orai-dependent Ca²⁺ signaling 3 to 4 days postinjury. Astrocyte-specific suppression of Stim and Orai completely inhibited the development of thermal allodynia 7 days after injury and also inhibited the loss of GABAergic inhibitory neurons required for CS in flies as well as mammals. Finally, constitutive SOCE-mediated astrocyte Ca²⁺ signaling resulted in thermal allodynia even in the absence of injury.

Astrocyte SOCE is necessary and sufficient for CS and thermal allodynia in Drosophila, adding key new understanding to the conserved astrocyte Ca²⁺ signaling mechanisms involved in development of neuropathic pain.