GPR37L1 identifies spinal cord astrocytes and protects neuropathic pain after nerve injury

Astrocytes in the spinal cord dorsal horn (SDH) play a pivotal role in synaptic transmission and neuropathic pain. However, the precise classification of SDH astrocytes in health and disease remains elusive. Here, we reveal Gpr37l1 as a marker and functional regulator of spinal astrocytes. Through single-nucleus RNA sequencing, we identified Gpr37l1 as a selective G-protein-coupled receptor (GPCR) marker for spinal cord astrocytes. Notably, SDH displayed reactive astrocyte phenotypes and exacerbated neuropathic pain following nerve injury combined with Gpr37l1 deficiency. In naive animals, Gpr37l1 knockdown in SDH astrocytes induces astrogliosis and pain hypersensitivity, while Gpr37l1^-/- mice fail to recover from neuropathic pain. GPR37L1 activation by maresin 1 increased astrocyte glutamate transporter 1 (GLT-1) activity and reduced spinal EPSCs and neuropathic pain. Selective overexpression of Gpr37l1 in SDH astrocytes reversed neuropathic pain and astrogliosis after nerve injury. Our findings illuminate astrocyte GPR37l1 as an essential negative regulator of pain, which protects against neuropathic pain through astrocyte signaling in SDH.