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Mediation of Exoticin analgesia by a truncated 6-transmembrane of the mu-opioid receptor
  • Fenfen Qin,
  • Zhigang Lu
Fenfen Qin
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.