2. Academic Validation
  3. Ignavine: a novel allosteric modulator of the μ opioid receptor

Ignavine: a novel allosteric modulator of the μ opioid receptor

  • Sci Rep. 2016 Aug 17:6:31748. doi: 10.1038/srep31748.
Katsuya Ohbuchi 1 2,  Chika Miyagi 1 2,  Yasuyuki Suzuki 1,  Yasuharu Mizuhara 1,  Keita Mizuno 1,  Yuji Omiya 1,  Masahiro Yamamoto 1,  Eiji Warabi 3,  Yuka Sudo 2 4,  Akinobu Yokoyama 2 4,  Kanako Miyano 2,  Takatsugu Hirokawa 5 6,  Yasuhito Uezono 2 7
Affiliations

Affiliations

  • 1 Tsumura Research Laboratories, Tsumura and Co., 3586 Yoshiwara, Ami-machi Inashiki-gun, Ibaraki 300-1192, Japan.
  • 2 Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
  • 3 Environmental Molecular Biology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan.
  • 4 Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-0022, Japan.
  • 5 Molecular Profiling Research Center for Drug Discovery, AIST Tokyo Waterfront Bio-IT Research Building 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
  • 6 Dicision of Biomedical Science, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan.
  • 7 Division of Supportive Care Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
PMID: 27530869 DOI: 10.1038/srep31748
Abstract

Processed Aconiti tuber (PAT) is used to treat pain associated with various disorders. Although it has been demonstrated that the κ Opioid Receptor (KOR) signaling pathway is a mediator of the analgesic effect of PAT, active components affecting opioid signaling have not yet been identified. In this study, we explored candidate components of PAT by pharmacokinetic analysis and identified ignavine, which is a different structure from aconitine Alkaloids. A receptor binding assay of opioid receptors showed that ignavine specifically binds the μ Opioid Receptor (MOR), not the KOR. Receptor internalization assay in MOR-expressing cell lines revealed that ignavine augmented the responses produced by D-Ala(2)-N-Me-Phe(4)-Gly-ol(5)-enkephalin (DAMGO), a representative MOR agonist, at a low concentration and inhibited it at a higher concentration. Ignavine also exerted positive modulatory activity for DAMGO, endomorphin-1 and morphine in cAMP assay. Additionally, ignavine alone showed an analgesic effect in vivo. In silico simulation analysis suggested that ignavine would induce a unique structural change distinguished from those induced by a representative MOR agonist and antagonist. These data collectively suggest the possibility that ignavine could be a novel allosteric modulator of the MOR. The present results may open the way for the development of a novel pain management strategy.

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