Spinal cord stimulation alleviates cognitive deficits in chronic pain by targeting the microglial lnc-PCM1/PKC/IFN-γ axis to resolve neuroinflammation

Background: Neuroinflammation plays a pivotal role in chronic pain with cognitive dysfunction (CPCD), a debilitating condition where effective treatments are limited. While spinal cord stimulation (SCS) is an established analgesic therapy, its potential to ameliorate cognitive deficits via central immunomodulation remains largely unexplored. Methods: A rat model of CPCD was established by spared nerve injury (SNI). We employed RNA sequencing to identify SCS-regulated long non-coding RNAs (lncRNAs) in the prefrontal cortex (PFC). The functional role of a specific microglial lncRNA, lnc-PCM1, was investigated using adeno-associated virus (AAV)-mediated approaches, behavioral tests, molecular assays, and primary cell co-cultures. Results: SCS treatment significantly improved cognitive function in CPCD rats. We identified lnc-PCM1 as a key mediator, predominantly expressed in microglia, whose expression was suppressed by SCS. Mechanistically, SCS-mediated inhibition of lnc-PCM1 upregulated its target PCM1, thereby attenuating the protein kinase C (PKC) phosphorylation / interferon-gamma (IFN-γ) signaling axis. This led to a reduction in microglial M1 polarization and pro-inflammatory cytokine release. Consequently, SCS mitigated IFN-γ-driven neuronal oxidative stress, apoptosis, and synaptic damage in the PFC. Critically, the therapeutic benefits of SCS on cognition and neuroinflammation were abolished by overexpressing lnc-PCM1 or knocking down PCM1. Conclusions: Our study unveils a novel immunomodulatory mechanism of SCS: it ameliorates CPCD by resolving neuroinflammation through targeting the microglial lnc-PCM1/PKC/IFN-γ pathway. These findings position lnc-PCM1 as a promising new target for immunopharmacological interventions in chronic pain-related cognitive disorders. This cascade not only inhibited microglial pro-inflammatory activation but also restored PFC neuronal synaptic integrity, which collectively contributed to cognitive rescue.