Palmitoylation of δ-catenin is critical to synapse plasticity and memory formation. We found that δ-catenin palmitoylation is also instrumental in the development of neuropathic pain. The abundances of palmitoylated δ-catenin and the palmitoyl acyltransferase DHHC3 were increased in dorsal root ganglion (DRG) sensory neurons in rat models of neuropathic pain. Inhibiting palmitoyl acyltransferases or decreasing δ-catenin abundance in the DRG by intrathecal injection of 2-bromopalmitate or shRNA, respectively, alleviated oxaliplatin or nerve injury–induced neuropathic pain in the rats. The palmitoylation of δ-catenin, which was induced by the inflammatory cytokine TNF-α, facilitated its interaction with the voltage-gated sodium channel Na_v1.6 and the kinesin motor protein KIF3A, which promoted the trafficking of Na_v1.6 to the plasma membrane in DRG neurons and contributed to mechanical hypersensitivity and allodynia in rats. These findings suggest that a palmitoylation-mediated KIF3A/δ-catenin/Na_v1.6 complex enhances the transmission of mechanical and nociceptive signals; thus, blocking this mechanism may be therapeutic in patients with neuropathic pain.

δ-连环蛋白的棕榈酰化对于突触可塑性和记忆形成至关重要。我们发现δ-连环蛋白棕榈酰化在神经性疼痛的发展中也起作用。在神经性疼痛大鼠模型的背根神经节（DRG）感觉神经元中，棕榈酰化的δ-catenin和棕榈酰酰基转移酶DHHC3的含量增加。通过鞘内注射2-溴棕榈酸酯或shRNA分别抑制DRG中的棕榈酰酰基转移酶或降低DRG中的δ-catenin丰度，减轻了奥沙利铂或神经损伤引起的大鼠神经性疼痛。炎性细胞因子TNF-α诱导的δ-catenin的棕榈酰化促进了其与电压门控钠通道Na _v的相互作用1.6和驱动蛋白马达蛋白KIF3A，促进钠贩卖_v 1.6在DRG神经元质膜，并有助于在大鼠机械性超敏反应和异常性疼痛。这些发现表明，棕榈酰化介导的KIF3A /δ-catenin/ Na _v 1.6复合物增强了机械和伤害性信号的传递。因此，阻断这种机制可能对神经性疼痛患者具有治疗作用。