Key Laboratory of Brain Function and Disease of Chinese Academy of Science, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, 230027, China.
Institute of Health Sciences and technology, School of Life Sciences, Anhui University, Hefei, Anhui, 2300601, China.
Transl Psychiatry. 2018 May 21;8(1):100. doi: 10.1038/s41398-018-0152-4.
Recent studies have shown that persistent pain facilitates the response to morphine reward. However, the circuit mechanism underlying this process remains ambiguous. In this study, using chronic constriction injury (CCI) of the sciatic nerve in mice, we found that persistent neuropathic pain reduced the minimum number of morphine conditioning sessions required to induce conditioned place preference (CPP) behavior. This dose of morphine had no effect on the pain threshold. In the medial prefrontal cortex (mPFC), which is involved in both pain and emotion processing, corticotropin-releasing factor (CRF) expressing neuronal activity was increased in CCI mice. Chemogenetic inhibition of mPFC CRF neurons reversed CCI-induced morphine CPP facilitation. Furthermore, the nucleus acumens (NAc) received mPFC CRF functional projections that exerted excitatory effects on NAc neurons. Optogenetic inhibition of mPCF neuronal terminals or local infusion of the CRF receptor 1 (CRFR1) antagonist in the NAc restored the effects of neuropathic pain on morphine-induced CPP behavior, but not in normal mice. On a molecular level, in CCI mice, CRFR1 protein expression was increased in the NAc by a histone dimethyltransferase G9a-mediated epigenetic mechanism. Local G9a knockdown increased the expression of CRFR1 and mimicked CCI-induced hypersensitivity to acquiring morphine CPP. Taken together, these findings demonstrate a previously unknown and specific mPFC CRF engagement of NAc neuronal circuits, the sensitization of which facilitates behavioral responses to morphine reward in neuropathic pain states via CRFR1s.
最近的研究表明，持续性疼痛促进了吗啡奖赏的反应。然而，这一过程的电路机制仍不清楚。在这项研究中，我们使用慢性坐骨神经缩窄损伤（CCI）的小鼠模型，发现持续性神经病理性疼痛减少了诱导条件性位置偏好（CPP）行为所需的最低吗啡条件性训练次数。这种剂量的吗啡对痛阈没有影响。在涉及疼痛和情绪处理的内侧前额叶皮层（mPFC）中，促肾上腺皮质激素释放因子（CRF）表达神经元的活性在 CCI 小鼠中增加。mPFC CRF 神经元的化学遗传抑制逆转了 CCI 诱导的吗啡 CPP 促进作用。此外，伏隔核（NAc）接收来自 mPFC CRF 的功能投射，对 NAc 神经元施加兴奋作用。mPCF 神经元末梢的光遗传抑制或 NAc 中 CRF 受体 1（CRFR1）拮抗剂的局部输注恢复了神经病理性疼痛对吗啡诱导的 CPP 行为的影响，但在正常小鼠中没有。在分子水平上，在 CCI 小鼠中，NAc 中的 CRFR1 蛋白表达通过组蛋白二甲基转移酶 G9a 介导的表观遗传机制增加。局部 G9a 敲低增加了 CRFR1 的表达，并模拟了 CCI 诱导的对获得吗啡 CPP 的敏感性增加。总之，这些发现表明，mPFC CRF 参与了以前未知的 NAc 神经元回路，其敏化作用通过 CRFR1 促进了神经病理性疼痛状态下对吗啡奖赏的行为反应。
