The neuron-restrictive silencing factor NRSF/REST binds to neuron-restrictive silencing elements in neuronal genes and recruits corepressors such as mSin3 to inhibit epigenetically neuronal gene expression. Because dysregulation of NRSF/REST is related to neuropathic pain, here, we have designed compounds to target neuropathic pain based on the mSin3-binding helix structure of NRSF/REST and examined their ability to bind to mSin3 by NMR. One compound, mS-11, binds strongly to mSin3 with a binding mode similar to that of NRSF/REST. In a mouse model of neuropathic pain, mS-11 was found to ameliorate abnormal pain behavior and to reverse lost peripheral morphine analgesia. Furthermore, even in the less well epigenetically defined case of fibromyalgia, mS-11 ameliorated symptoms in a mouse model, suggesting that fibromyalgia is related to the dysfunction of NRSF/REST. Taken together, these findings show that the chemically optimized mimetic mS-11 can inhibit mSin3-NRSF/REST binding and successfully reverse lost peripheral and central morphine analgesia in mouse models of pain.

神经元限制性沉默因子NRSF / REST与神经元基因中的神经元限制性沉默元件结合，并募集mRNA抑制剂mSin3以抑制表观遗传学的神经元基因表达。由于NRSF / REST的失调与神经性疼痛有关，因此，在此，我们基于NRSF / REST的mSin3结合螺旋结构设计了靶向神经性疼痛的化合物，并通过NMR检测了它们与mSin3结合的能力。一种化合物mS-11以类似于NRSF / REST的结合模式与mSin3牢固结合。在神经性疼痛的小鼠模型中，发现mS-11可改善异常疼痛行为并逆转失去的外周吗啡镇痛作用。此外，即使在表观遗传学上定义较差的纤维肌痛病例中，mS-11也会改善小鼠模型中的症状，提示纤维肌痛与NRSF / REST的功能障碍有关。综上所述，这些发现表明，化学优化的模拟物mS-11可以抑制mSin3-NRSF / REST结合并成功逆转小鼠疼痛模型中失去的外周和中枢吗啡镇痛作用。