BACKGROUND Neuropathic pain is one of the most debilitating of all chronic pain syndromes. Intrathecal (i.t.) bone marrow stromal cell (BMSC) injections have a favorable safety profile; however, results have been inconsistent, and complete understanding of how BMSCs affect neuropathic pain remains elusive. METHODS We evaluated the analgesic effect of BMSCs on neuropathic pain in a chronic compression of the dorsal root ganglion (CCD) model. We analyzed the effect of BMSCs on microglia reactivity and expression of purinergic receptor P2X4 (P2X4R). Furthermore, we assessed the effect of BMSCs on the expression of transient receptor potential vanilloid 4 (TRPV4), a key molecule in the pathogenesis of neuropathic pain, in dorsal root ganglion (DRG) neurons. RESULTS I.t. BMSC transiently but significantly ameliorated neuropathic pain behavior (37.6% reduction for 2 days). We found no evidence of BMSC infiltration into the spinal cord parenchyma or DRGs, and we also demonstrated that intrathecal injection of BMSC-lysates provides similar relief. These findings suggest that the analgesic effects of i.t. BMSC were largely due to the release of BMSC-derived factors into the intrathecal space. Mechanistically, we found that while i.t. BMSCs did not change TRPV4 expression in DRG neurons, there was a significant reduction of P2X4R expression in the spinal cord microglia. BMSC-lysate also reduced P2X4R expression in activated microglia in vitro. Coadministration of additional pharmacological interventions targeting P2X4R confirmed that modulation of P2X4R might be a key mechanism for the analgesic effects of i.t. BMSC. CONCLUSION Altogether, our results suggest that i.t. BMSC is an effective and safe treatment of neuropathic pain and provides novel evidence that BMSC's analgesic effects are largely mediated by the release of BMSC-derived factors resulting in microglial P2X4R downregulation.

中文翻译：

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鞘内注射骨髓基质细胞可通过抑制脊髓小胶质细胞中的P2X4R减轻神经性疼痛。

背景技术神经性疼痛是所有慢性疼痛综合征中最使人衰弱的一种。鞘内（骨髓）骨髓基质细胞（BMSC）注射具有良好的安全性。然而，结果并不一致，并且对BMSCs如何影响神经性疼痛的全面了解仍然遥遥无期。方法我们评估了在慢性压迫背根神经节（CCD）模型中BMSC对神经性疼痛的镇痛作用。我们分析了骨髓间充质干细胞对小胶质细胞反应性和嘌呤能受体P2X4（P2X4R）表达的影响。此外，我们评估了骨髓间充质干细胞对背根神经节（DRG）神经元中神经性疼痛发病机制中的关键分子瞬时受体电位香草酸4（TRPV4）的表达的影响。结果BMSC短暂但明显改善了神经性疼痛行为（37。2天减少6％）。我们没有发现BMSC浸入脊髓实质或DRGs的证据，并且我们还证明鞘内注射BMSC裂解物可提供类似的缓解作用。这些发现表明，其BMSC的镇痛作用主要归因于BMSC衍生的因子释放到鞘内空间。从机制上讲，我们发现虽然BMSCs不会改变DRG神经元中TRPV4的表达，但脊髓小胶质细胞中P2X4R的表达却明显降低。在体外，BMSC裂解物还降低了活化的小胶质细胞中P2X4R的表达。共同施用针对P2X4R的其他药物干预措施证实，调节P2X4R可能是其BMSC镇痛作用的关键机制。结论总之，我们的结果表明