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Mediation of Exoticin analgesia by a truncated 6-transmembrane of the mu-opioid receptor
  • +11
  • Fenfen Qin,
  • Qisheng Wang,
  • Anlong Liu,
  • Yongwei Jiang,
  • Zhonghao Li,
  • Han Zhang,
  • Dengyun Nie,
  • Qingyang Liu,
  • Hui Wang,
  • Shang Lu,
  • Qian Li,
  • Jian Liu,
  • Shengfeng Lu,
  • Zhigang Lu
Fenfen Qin
Nanjing University of Chinese Medicine
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Qisheng Wang
Nanjing University of Chinese Medicine
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Anlong Liu
Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
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Yongwei Jiang
Nanjing University of Chinese Medicine
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Zhonghao Li
Nanjing University of Chinese Medicine
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Han Zhang
Nanjing University of Chinese Medicine
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Dengyun Nie
Nanjing University of Chinese Medicine
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Qingyang Liu
Nanjing University of Chinese Medicine
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Hui Wang
Nanjing University of Chinese Medicine
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Shang Lu
Nanjing University of Chinese Medicine
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Qian Li
Nanjing University of Chinese Medicine
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Jian Liu
Nanjing University of Chinese Medicine
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Shengfeng Lu
Nanjing University of Chinese Medicine
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Zhigang Lu
Nanjing University of Chinese Medicine
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Abstract

Background and Purpose:Mu-opioids remain vastly important for pain treatment, and would represent ideal analgesics if their analgesic effects could be separated from their many side effects.Exoticin, an extract of Murraya exotica, has been shown to have an analgesic effect which can be blocked by naloxone.Here, we hypothesized that the analgesic effect of Exoticin is mediated by 6-transmembrane (6TM) of the mu-opioid receptor. Experimental Approach:We determines the analgesic EC50 of Exoticin by using the hot-plate assay.The analgesia of Exoticin was evaluated after intrathecal administration with mu, delta, and kappa antagonists in C57BL/6 mice. Antinociceptive effects of Exoticin on formalin or Complete Freund’s adjuvant (CFA) mediated allodynia and heat-hyperalgesia were assessed in exon 11 mu-opioid knockout (E11 KO) and exon 1/ exon 11 mu-opioid double knockout (E1/E11 KO) mice. Opioid-related side effects, such as respiration depression, constipation, locomotor activity and dependence were assessed.Finally, to verify the effect of 6TM on Exoticin, the analgesic effect of Exoticin mediated by 6TM of the mu-opioid receptor was determined by over-expression of the adeno-associated virus (AAV) in E1/E11KO mu-opioid mice. Key Results:Delta, kappa antagonists in WT mice had no impact on Exoticin analgesia, while mice which received the mu antagonist markedly lowered. Loss of the truncated 6TM variants in the E11 KO mouse eliminated Exoticin analgesia. Restoring expression of a 6TM variant with an AAV-mMor-1G rescued Exoticin analgesia in E1/E11 KO mouse that no expressed the 7-transmembrane (7TM) variants. Conclusion and Implications:Exoticin analgesia depended upon the expression of exon 11-associated truncated 6TM variants of mu-opioid receptor.