Spinal Cord Stimulation Attenuates Cognitive Deficits in Chronic Pain in Association with Modulation of the Microglial lnc-PCM1/PCM1/PKC/IFN-γ Signaling Network.

Abstract

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. A rat model of CPCD was generated by spared nerve injury (SNI). RNA sequencing was used to identify SCS-regulated long non-coding RNAs (lncRNAs) in the prefrontal cortex (PFC). The functional involvement of the candidate microglial transcript NONRATT012007.2 (hereafter termed lnc-PCM1) was examined using adeno-associated virus (AAV)-mediated manipulation, behavioral testing, molecular assays, and primary-cell conditioned-medium experiments. SCS improved cognitive performance in CPCD rats. lnc-PCM1 was predominantly expressed in microglia and was reduced after SCS. Lower lnc-PCM1 expression was accompanied by increased pericentriolar material 1 (PCM1), reduced protein kinase C (PKC) phosphorylation and IFN-γ abundance, less M1-polarized microglial activation, and lower pro-inflammatory cytokine release. Conditioned medium from manipulated microglia produced corresponding changes in neuronal oxidative stress, mitochondrial membrane potential, apoptosis-related proteins, and synaptic markers. In vivo overexpression of lnc-PCM1 or knockdown of PCM1 partially attenuated the cognitive and neuroinflammatory effects associated with SCS. The findings support an association between the cognitive effects of SCS and modulation of a microglial lnc-PCM1/PCM1/PKC/IFN-γ signaling network in the PFC. Because formal epistasis and IFN-γ neutralization or receptor-blockade experiments were not performed, the directionality and IFN-γ dependence of this network remain to be established.