Xu Jing, Yan Zihan, Bang Sangsu, Velmeshev Dmitry, Ji Ru-Rong
Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Neuron. 2025 Apr 16;113(8):1206-1222.e6. doi: 10.1016/j.neuron.2025.01.012. Epub 2025 Feb 13.
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.
脊髓背角（SDH）中的星形胶质细胞在突触传递和神经性疼痛中起关键作用。然而，健康和疾病状态下SDH星形胶质细胞的精确分类仍不清楚。在此，我们揭示了Gpr37l1作为脊髓星形胶质细胞的标志物和功能调节因子。通过单核RNA测序，我们确定Gpr37l1是脊髓星形胶质细胞的一种选择性G蛋白偶联受体（GPCR）标志物。值得注意的是，在神经损伤并伴有Gpr37l1缺陷后，SDH表现出反应性星形胶质细胞表型并加剧了神经性疼痛。在未受伤的动物中，SDH星形胶质细胞中Gpr37l1的敲低会诱导星形胶质细胞增生和疼痛超敏反应，而Gpr37l1基因敲除小鼠无法从神经性疼痛中恢复。maresin 1对GPR37L1的激活增加了星形胶质细胞谷氨酸转运体1（GLT-1）的活性，并减少了脊髓兴奋性突触后电流和神经性疼痛。在SDH星形胶质细胞中选择性过表达Gpr37l1可逆转神经损伤后的神经性疼痛和星形胶质细胞增生。我们的研究结果表明，星形胶质细胞GPR37l1是疼痛的重要负调节因子，它通过SDH中的星形胶质细胞信号传导来预防神经性疼痛。
