Zeng Yeting, Luo Huoqing, Gao Zilong, Zhu Xiaona, Shen Yinbo, Li Yulong, Hu Ji, Yang Jiajun
Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
iScience. 2021 Feb 20;24(3):102213. doi: 10.1016/j.isci.2021.102213. eCollection 2021 Mar 19.
Morphine is commonly used to relieve moderate to severe pain, but repeated doses cause opioid tolerance. Here, we used ATP sensor and fiber photometry to detect prefrontal ATP level. It showed that prefrontal ATP level decreased after morphine injection and the event amplitude tended to decrease with continuous morphine exposure. Morphine had little effect on prefrontal ATP due to its tolerance. Therefore, we hypothesized that the analgesic effect of morphine might be related to ATP in the medial prefrontal cortex (mPFC). Moreover, local infusion of ATP partially antagonized morphine analgesia. Then we found that inhibiting P2X7R in the mPFC mimicked morphine analgesia. In morphine-tolerant mice, pretreatment with P2X4R or P2X7R antagonists in the mPFC enhanced analgesic effect. Our findings suggest that reduction of prefrontal purinergic signaling is necessary for the morphine analgesia, which help elucidate the mechanism of morphine analgesia and may lead to the development of new clinical treatments for neuropathic pain.
吗啡常用于缓解中度至重度疼痛，但重复给药会导致阿片类药物耐受性。在此，我们使用ATP传感器和光纤光度法检测前额叶ATP水平。结果显示，注射吗啡后前额叶ATP水平降低，且随着吗啡持续暴露，事件幅度趋于下降。由于耐受性，吗啡对前额叶ATP影响不大。因此，我们推测吗啡的镇痛作用可能与内侧前额叶皮质（mPFC）中的ATP有关。此外，局部注入ATP可部分拮抗吗啡镇痛作用。然后我们发现，抑制mPFC中的P2X7R可模拟吗啡镇痛效果。在吗啡耐受小鼠中，在mPFC中用P2X4R或P2X7R拮抗剂预处理可增强镇痛效果。我们的研究结果表明，前额叶嘌呤能信号的减少是吗啡镇痛所必需的，这有助于阐明吗啡镇痛的机制，并可能导致开发用于神经性疼痛的新临床治疗方法。
