Reduction of prefrontal purinergic signaling is necessary for the analgesic effect of morphine
Yeting Zeng,
Huoqing Luo,
Zilong Gao,
Xiaona Zhu,
Yinbo Shen,
Yulong Li,
Ji Hu,
Jiajun Yang
Affiliations
Yeting Zeng
Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
Huoqing Luo
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Zilong Gao
Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Chinese Institute for Brain Research, Beijing (CIBR), Beijing 102206, China
Xiaona Zhu
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Yinbo Shen
Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
Yulong Li
Chinese Institute for Brain Research, Beijing (CIBR), Beijing 102206, China; State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing 100871, China; PKU-IDG/McGovern Institute for Brain Research, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
Ji Hu
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, 200030, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226019, China; Corresponding author
Jiajun Yang
Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; Corresponding author
Summary: 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.
