BRAF recruitment to spinal sensory synapses promotes neuropathic pain by potentiating transsynaptic NMDA receptor activity.

Sustained hyperactivity of synaptic NMDA receptors (NMDARs) in the spinal dorsal horn is a hallmark of chronic neuropathic pain. Here, we identified the kinase BRAF as a critical regulator of this process. Spinal nerve injury in rats induced the translocation of BRAF from the dorsal root ganglion (DRG) to spinal cord synaptosomes, which was associated with enhanced phosphorylation of the downstream kinases MEK and ERK. In addition, spinal cord injury increased the interaction between NMDARs and BRAF/MEK/ERK in spinal cord samples from rats and humans. Pharmacological inhibition or genetic ablation of BRAF in mouse DRG neurons reversed nerve injury-induced NMDAR phosphorylation, synaptic trafficking, and presynaptic and postsynaptic hyperactivity in the spinal dorsal horn. Furthermore, whereas pain hypersensitivity persisted in wild-type mice after nerve injury, it was transient and less severe in mice that either lacked BRAF in DRG neurons or were treated with BRAF pathway inhibitors. Conversely, expressing a constitutively active BRAF mutant in DRG neurons induced sustained nociceptive hypersensitivity, which was blocked by NMDAR antagonists, gabapentin, or an α2δ-1 C-terminal-interfering peptide. This was accompanied by increased NMDAR phosphorylation and enhanced pre- and postsynaptic activity in the spinal cord. These findings reveal that BRAF in sensory neurons promotes neuropathic pain by enhancing NMDAR phosphorylation and transsynaptic hyperactivity and suggest that BRAF inhibitors might be repurposed to treat neuropathic pain.