PTP1B in dorsal root ganglion nociceptors drives neuropathic pain via a presynaptic Src/GluN2B signaling pathway

BACKGROUND: Neuropathic pain, a debilitating chronic condition, remains a major clinical challenge due to its complex pathogenesis and limited treatment options. Protein tyrosine phosphatase 1B (PTP1B), a key regulator of tyrosine phosphorylation, has been implicated in various diseases, yet its specific role and mechanism in nociceptive processing within the dorsal root ganglion (DRG) are poorly understood. METHODS: To investigate this, we used peripheral nerve injury models to assess PTP1B expression in the DRG. We employed nociceptor-specific overexpression and targeted knockdown of PTP1B to evaluate its effect on neuropathic pain-like behaviors, including mechanical allodynia and negative affect. Furthermore, we used electrophysiological recordings of miniature excitatory postsynaptic currents and pharmacological inhibition targeting Src kinase and N-methyl-D-aspartate (NMDA) receptor GluN2B to delineate the underlying molecular mechanisms. RESULTS: Peripheral nerve injury induced a sustained upregulation of PTP1B predominantly in non-peptidergic nociceptors of the DRG. Mimicking this upregulation through nociceptor-specific overexpression elicited robust neuropathic pain-like behaviors. Conversely, targeted PTP1B knockdown therapeutically reversed established pain hypersensitivity. Mechanistically, PTP1B interacted with and activated Src kinase by dephosphorylating its inhibitory site at Tyr529. This led to enhanced phosphorylation of the NMDA receptor GluN2B subunit at Tyr1472, increasing presynaptic glutamate release in the spinal dorsal horn, as evidenced by elevated miniature excitatory postsynaptic currents. Consequently, pharmacological inhibition of either GluN2B or Src largely reversed PTP1B-driven pain sensitization. CONCLUSIONS: Our findings identified PTP1B in DRG nociceptors as a critical upstream regulator of the presynaptic Src/GluN2B pathway, establishing it as a promising therapeutic target for the treatment of neuropathic pain.