Kidney and brain-expressed protein upregulation in the anterior cingulate cortex mediates chronic post-thoracotomy pain by the phospho-protein kinase Mζ/glutamate receptor 1 signaling pathway and neuroinflammation in male rats

Chronic post-thoracotomy pain (CPTP), affecting approximately 50% of patients after thoracotomy, poses a substantial socioeconomic burden with an unclear mechanism. This study investigated the role of kidney and brain-expressed protein (KIBRA) in the contralateral anterior cingulate gyrus (ACC)-a key pain processing region-in a male rat model of CPTP. We found that KIBRA mediates CPTP generation by activating the phosphorylated protein kinase Mζ (p-PKMζ)/glutamate receptor 1 (GluR1) pathway and promoting neuroinflammation. Local application of KIBRA short hairpin RNA in the ACC alleviated postoperative pain, reduced the mechanical hyperalgesia ratio (from 50% to 38%), and downregulated expression of KIBRA, p-PKMζ, GluR1, tumor necrosis factor-α, and interleukin-1β in the ACC neurons. Conversely, ACC overexpression of KIBRA recapitulated CPTP, inducing chest wall hyperalgesia (∼60%) and enhancing the aforementioned pathway and inflammatory markers. Notably, KIBRA overexpression increased CPTP incidence to 100% in thoracotomy rats, with elevated levels of KIBRA, p-PKMζ, GluR1, tumor necrosis factor-α, and interleukin-1β compared with CPTP alone. Administration of the PKMζ inhibitor zeta inhibitory peptide alleviated pain induced by both thoracotomy and KIBRA overexpression. Patch-clamp recordings revealed that zeta inhibitory peptide inhibited the amplitude of evoked excitatory postsynaptic currents (EPSCs) and the frequency of miniature EPSCs in CPTP and KIBRA overexpression groups. These results demonstrate that KIBRA in ACC neurons significantly contributes to CPTP by p-PKMζ/GluR1 and neuroinflammation, offering novel mechanistic insights. However, as the study was conducted exclusively in male animals, and studies in clinical settings have shown that the CPTP prevalence is higher among females, the findings primarily apply to males, underscoring the need for future sex-specific investigations.