r their technical assistance. The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: <http://www.textcheck.com/certificate/A7UxHP>.

T. Shimakami, S.K. and T.O. conceived the study and designed the experiments. T.N., N.N., T. Shirakura, C.M., Y.N., F.Z., L.X., G.C. and M.N. performed the experiments. T.N., N.N. and T. Shirakura analyzed and interpreted data of the animal experiment. T.N., T. Shimakami, Taro Y., Y.S., Tatsuya Y., E.M. and M.H. contributed to the acquisition and analysis of clinical data. T.N. and N.N. wrote the manuscript. T. Shimakami, Taro Y., Y.S., Tatsuya Y., E.M. and M.H. contributed to discussions. S.K. and T.O. contributed to discussions and edited the manuscript. T.O. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis.

No datasets were generated or analyzed during the current study.

The authors declare no competing interests.


1. Introduction
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Many attempts have been made to use breeding or molecular biological methods to modify the ability to produce secondary metabolites in medicinal plants. Among the challenges being addressed, manipulations of the morphine biosynthesis in the opium poppy (*Papaver somniferum* L.), particularly the conversion of narcotic morphine to codeine, which is of high importance as an antitussive and a synthetic source of dihydrocodeine, or to thebaine, which is also an important starting material for the semi-synthesis of the analgesic oxycodone, will contribute to the control of narcotics, and to the supply of useful alkaloids for the production of pharmaceuticals.

The gradual elucidation of enzymology of the alkaloid biosynthesis in *P. somniferum* led to genetical engineering of alkaloid biosynthetic pathway using native genes. The first report was on the introduction of a gene encoding berberine bridge enzyme (BBE) to *P