Protein tyrosine phosphatase 1B contributes to neuropathic pain by aggravating NF-κB and glial cells activation-mediated neuroinflammation via promoting endoplasmic reticulum stress

BackgroundNeuropathic pain is a prevalent and highly debilitating condition that impacts millions of individuals globally. Neuroinflammation is considered a key factor in the development of neuropathic pain. Accumulating evidence suggests that protein tyrosine phosphatase 1B (PTP1B) plays a crucial role in regulating neuroinflammation. Nevertheless, the specific involvement of PTP1B in neuropathic pain remains largely unknown. This study aims to examine the impact of PTP1B on neuropathic pain and unravel the underlying molecular mechanisms implicated.MethodsIn the current study, we evaluated the paw withdrawal threshold (PWT) of male rats following spared nerve injury (SNI) to assess the presence of neuropathic pain. To elucidate the underlying mechanisms, western blotting, immunofluorescence, and electron microscopy techniques were employed.ResultsOur results showed that SNI significantly elevated PTP1B levels, which was accompanied by an increase in the expression of endoplasmic reticulum (ER) stress markers (BIP, p-PERK, p-IRE1 alpha, and ATF6) and phosphorylated NF-kappa B in the spinal dorsal horn. SNI-induced mechanical allodynia was impaired by the treatment of intrathecal injection of PTP1B siRNA or PTP1B-IN-1, a specific inhibitor of PTP1B. Moreover, the intrathecal administration of PTP1B-IN-1 effectively suppressed the expression of ER stress markers (BIP, p-PERK/p-eIF2 alpha, p-IRE1 alpha, and ATF6), leading to the inhibition of NF-kappa B, microglia, and astrocytes activation, as well as a decrease in pro-inflammatory cytokines, including TNF-alpha, IL-6, and IL-1 beta. However, these effects were reversed by intrathecal administration of tunicamycin (Tm, an inducer of ER stress). Additionally, intrathecal administration of Tm in healthy rats resulted in the development of mechanical allodynia and the activation of NF-kappa B-mediated neuroinflammatory signaling.ConclusionsThe upregulation of PTP1B induced by SNI facilitates the activation of NF-kappa B and glial cells via ER stress in the spinal dorsal horn. This, in turn, leads to an increase in the production of pro-inflammatory cytokines, thereby contributing to the development and maintenance of neuropathic pain. Therefore, targeting PTP1B could be a promising therapeutic strategy for the treatment of neuropathic pain. Schematic illustration of the role of PTP1B in neuropathic pain. PTP1B promotes ER stress, leading to activation of NF-kappa B, microglia, and astrocytes, and increased production of pro-inflammatory cytokines TNF-alpha, IL-6, and IL-1 beta, thus exacerbating mechanical pain caused by SNI.image