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Histone methylations play a crucial role in the development of neuropathic pain, and SET domain containing 2 (SETD2), a histone methyltransferase, serves as the sole tri-methylase known to catalyze H3K36me3 at the gene body. The N-methyl-d-aspartate receptor (NMDAR) is activated and mediates excitatory synaptic transmission in neuropathic pain. Nevertheless, the involvement of SETD2 in neuropathic pain and the specific regulatory mechanisms affecting NMDARs remain poorly understood. The expression levels of SETD2 were significantly decreased in the spinal cord and dorsal root ganglion (DRG) of rodents undergoing neuropathic pain induced by sciatic nerve chronic constrictive injury. Lentiviral shRNA-mediated SETD2 knockdown and conditional knockout in sensory neurons caused sustained NMDAR upregulation in DRG and spinal cord, which resulted in heightened neuronal excitability and increased pain hypersensitivity. SETD2 deficiency also led to reduced H3K36me3 deposition within the Grin1 (glutamate ionotropic receptor NMDA type subunit 1) gene body, thereby promoting aberrant transcription of the NMDARs subunit GluN1. The absence of SETD2 in the DRG potentiated neuronal excitability and increased presynaptic NMDAR activity in the spinal dorsal horn. Chromatin immunoprecipitation sequencing targeting H3K36me3 identified NFAT5 as a co-transcription factor in the transcriptional regulation of Grin1. These findings highlight SETD2 as a key regulator in pain signal transmission and offered new perspectives on the development of analgesics through the targeted modulation of epigenetic mechanisms.