PDGFR mediates lumbar spinal stenosis-induced neuropathic pain by regulating JAK2/STAT3 signaling in activated macrophages

Lumbar spinal stenosis (LSS) is one of the most common spinal disorders in elderly people and is often accompanied by neuropathic pain. Although our previous studies have demonstrated that infiltrating macrophage contribute to chronic neuropathic pain in LSS rat model, the molecular mechanisms underlying macrophage activation and infiltration have not been fully elucidated. In this study, we examined the critical role of platelet-derived growth factor receptor (PDGFR) signaling pathway in neuropathic pain associated with macrophage infiltration and activation in LSS rats. The LSS rat model was induced by cauda equina compression using a silicone block placed within the epidural spaces of the L5-L6 vertebrae, with neuropathic pain developing four weeks after compression. We found that the PDGFR and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathways were upregulated in infiltrated macrophages at 28 days in the LSS model. Administration of the PDGFR inhibitor imatinib significantly alleviated LSS-induced macrophages activation and infiltration. Imatinib also reduced LSS-induced chronic mechanical allodynia and inhibited the expression of inflammatory mediators including tumor necrosis factor alpha (TNF-α), interleukin beta (IL-1β), interleukin 6 (IL-6), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Furthermore, imatinib significantly alleviated the activation of RAW 264.7 macrophage cell line by lipopolysaccharide (LPS). These findings suggest that PDGFR signaling mediates neuropathic pain by promoting macrophage infiltration and activation following cauda equina compression and may serve as a potential therapeutic target for neuropathic pain in LSS patients.