Sparcl1/Hevin drives inflammatory and neuropathic pain through astrocyte and NMDA receptor signaling

Hevin/Sparcl1 is an astrocyte-secreted protein and regulates synapse formation in the brain. Here we show that astrocytic hevin signaling plays a critical role in maintaining chronic pain. Compared to wild-type mice, hevin-null mice exhibited normal mechanical and heat sensitivity but reduced inflammatory pain. Interestingly, hevin is required for the maintenance of nerve injury-induced neuropathic pain (mechanical allodynia), and hevin-null mice have faster recovery than wild-type mice from neuropathic pain after nerve injury. Intrathecal injection of wild-type hevin but not a hevin mutant that is no longer synaptogenic was sufficient to induce persistent mechanical allodynia in naïve mice and further enhanced neuropathic pain in animals with nerve injury. In hevin-null mice with nerve injury, AAV-mediated re-expression of hevin, but not mutant hevin, in GFAP-expressing spinal cord astrocytes could reinstate neuropathic pain. Mechanistically, hevin is crucial for spinal cord NMDA receptor (NMDAR) signaling, as NMDA-induced mechanical allodynia and inward currents in spinal cord lamina II neurons is reduced in hevin-null mice. Hevin potentiated NMDA currents mediated by the GluN2B-containing NMDARs. Furthermore, intrathecal injection of a neutralizing antibody against hevin alleviated acute inflammatory pain and persistent neuropathic pain. Secreted hevin was detected in mouse cerebrospinal fluid (CSF) and nerve injury significantly increased CSF hevin abundance. Finally, neurosurgery caused rapid (< 10 hours) and substantial increases (~20 fold) in HEVIN levels in human CSF. Collectively, our findings support a critical role of hevin and astrocytes in the maintenance of chronic pain. Neutralizing of secreted hevin with monoclonal antibody may provide a new therapeutic strategy for treating chronic pain and NMDAR-medicated neurodegeneration.