吗啡耐受是限制其临床镇痛应用的一大医学难题。我们前期研究发现,吗啡耐受大鼠腰段脊髓的长链非编码RNA(LncRNA)MRAK159688表达明显上调，有研究报道其与抑制元件1-沉默转录因子(REST，又称神经元限制性沉默因子，NRSF)相互作用，已有报道REST可以负向调控μ阿片受体(MOR)的表达。因此，我们提出假说：MRAK159688上调，激活REST转录调控，抑制MOR转录及表达，导致吗啡耐受形成。本项目将检测MRAK159688在背根神经节(DRG)及脊髓背角的时空表达，证实其同REST的相互作用。体内外干预MRAK159688，观察对下游MOR及行为学的影响。本项目从分子-细胞-整体动物行为学的研究角度揭示吗啡耐受发生发展的新机制，为阐明MRAK159688通过REST介导MOR下调参与吗啡耐受形成的分子机制提供实验依据，为开发新型镇痛药物提供新的靶点，具有重要的临床转化意义。

Morphine tolerance is a difficult problem that limits its clinical application. The molecular mechanism of morphine tolerance is still unclear. In our previous study, we used lncRNA array and found that the expression of MRAK159688 of the lumbar spinal dorsal horn in morphine tolerance rats was significantly up-regulated than that of control group. It has been reported to interact with the inhibitory element 1-silencing transcription factor (REST, also known as neuron-restricted silencing factor, NRSF), and it has been reported that REST negatively regulate the expression of μ opioid receptor (MOR). Therefore, we hypothesized that MRAK159688 is up-regulated, combined with REST transcription factors or coREST complex, activates REST transcriptional regulation, inhibits MOR transcription and expression, leading to morphine tolerance.This project will detect the temporal and spatial expression of MRAK159688 in the dorsal root ganglia (DRG) and spinal dorsal horn, confirming the interaction with REST. Interventional MRAK159688 in vitro and in vivo to observe the effects on downstream target gene (MOR) and behavior. This project reveals a new mechanism for the development of morphine tolerance from the perspective of molecular-cell-animal behavioral research, in order to provide an experimental basis for elucidating the molecular mechanism of MRAK159688 regulation of REST-mediated MOR down-regulation of morphine tolerance. The implementation of this project provides experimental evidence for the molecular mechanism that MRAK159688 regulates morphine tolerance and provides novel intervention targets for the prophylaxis and treatment of morphine tolerance.