INSERM, UMR S 713, Paris, France.
Gene Ther. 2009 Apr;16(4):476-82. doi: 10.1038/gt.2009.22. Epub 2009 Feb 26.
Activated glial cells in the dorsal spinal cord participate in the development and maintenance of pain after peripheral nerve injury. Our understanding of mechanisms involved in functional changes of spinal glia remains incomplete. Excepting drugs that completely disrupt glial function, pharmacological studies fail to target glia and to modify locally its function to really discriminate the function of neuronal versus glial cells in chronic pain. Lentivirus-derived vectors fulfill several criteria that make them potentially interesting for this preferential targeting of glial cells in the spinal cord. We showed that in vivo single microdelivery of vesicular stomatitis virus G pseudotyped lentiviral vectors into the rat dorsal spinal cord led to a highly preferential expression of transgenes in astrocytes and microglial cells. This local and glia-targeted intervention allowed, for instance, the blockade of intracellular nuclear factor kappaB signaling pathway leading then to downregulation of the enhanced expression of several markers related to inflammation and pain, and, finally, to prolonged antihyperalgesic and antiallodynic effects. Targeted modulation of the expression of gene of interest in glial cells, closely restricted to a particular region of the spinal cord, may thus represent an interesting approach to refine the understanding of mechanisms by which spinal glial cells participate in pain processing.
背根神经节激活的神经胶质细胞参与外周神经损伤后疼痛的发展和维持。我们对脊髓神经胶质细胞功能变化所涉及的机制的了解还不完全。除了能完全破坏神经胶质功能的药物外，药理学研究不能针对神经胶质细胞，并局部改变其功能，从而真正区分慢性疼痛中神经元与神经胶质细胞的功能。慢病毒衍生的载体满足了几个标准，使它们有可能成为脊髓中神经胶质细胞优先靶向的潜在靶点。我们表明，在体单微注射水疱性口炎病毒 G 假型慢病毒载体到大鼠背根神经节中，导致转基因在星形胶质细胞和小胶质细胞中高度优先表达。这种局部和神经胶质细胞靶向的干预，例如，可以阻断细胞内核因子 kappaB 信号通路，从而导致与炎症和疼痛相关的几种标记物的增强表达下调，最终导致抗痛觉过敏和抗痛觉过敏作用的延长。因此，对感兴趣的基因在神经胶质细胞中的表达进行靶向调节，严格限制在脊髓的特定区域内，可能是一种很好的方法，可以更深入地了解脊髓神经胶质细胞参与疼痛处理的机制。
