Toll样受体4在吗啡应用和耐受中的作用

Effects of Toll-like Receptor 4 in Morphine Administration and Tolerance

Toll样受体4(Toll-like receptor 4)是主要表达于小胶质细胞表面开启哺乳动物先天免疫反应的重要受体.近年研究表明,TLR4参与疼痛及炎症的形成.TLR4能够被吗啡激活,其结果导致小胶质细胞活化,细胞因子合成和释放增加,从而提高疼痛感受细胞的兴奋性,减小或抵消吗啡的镇痛作用,即形成吗啡耐受.抑制TLR4可以增加吗啡的镇痛作用,减缓吗啡耐受的形成.TLR4与经典阿片受体之间存在立体选择特异性差异,(-)和(+)吗啡均能使之激活.吗啡-TLR4-胶质细胞作用链的研究为治疗吗啡耐受产生提供新的路径.

Toll-like receptor 4（ TLR4） is mainly expressed on microglia in the central nervous system initiating the innate immune response in mammals. Recently,studies showed that TLR4 is involved in the pathogenesis of pain and inflammation. Morphine can activate TLR4. This results in the activation of microglia and increased synthesis and release of inflammatory cytokines,leading to the hyperexcitability of nociceptive neurons and reduction or abolishment of morphine-induced analgesia,i. e. morphine tolerance. Blockade of TLR4 can enhance the morphine analgesia and inhibit morphine tolerance. TLR4 differs from classical opioid receptors in that TLR4 does not display specific stereoselectivity for opioid ligands. Both（ ＋）- and（-）-morphine can activate TLR4 signaling. The study of interaction of morphine-TLR4-glia may provide a new therapy to inhibit morphine tolerance.