The activation of p66shc in the Prelimbic Cortex contributes to the development of neuropathic pain

This study investigated the role of the adaptor protein p66shc in the prelimbic cortex (PrL) in neuropathic pain development in rats. Results showed that activated p66shc and reactive oxygen species (ROS) were elevated in the PrL following peripheral nerve injury. Intra-PrL administration of p66shc siRNA significantly alleviated mechanical allodynia and reduced ROS levels, without impairing locomotor activity. Electrophysiological analysis revealed that neuropathic pain enhanced the excitability of PrL layer 2/3 pyramidal neurons, an effect reversed by p66shc inhibition. Furthermore, spared nerve injury (SNI) shifted synaptic transmission in these neurons, increasing miniature excitatory postsynaptic current (mEPSC) frequency and decreasing miniature inhibitory postsynaptic current (mIPSC) frequency. Both synaptic alterations were normalized by p66shc siRNA. Collectively, these findings indicate that p66shc in the PrL plays a crucial role in neuropathic pain pathogenesis and may represent a novel therapeutic target. • p66shc is upregulated and activated in the prelimbic cortex (PrL) following peripheral nerve injury. • PrL-targeted inhibition of p66shc alleviates pain and normalizes SNI-induced synaptic imbalance and neuronal hyperexcitability. • p66shc in the PrL represents a novel cortical target for neuropathic pain therapy.