• Yi-Han Huang, Yu-Wei Wu, Jian-Ying Chuang, Yung-Chiao Chang, Hsiao-Fu Chang, Pao-Luh Tao, Horace H Loh, and Shiu-Hwa Yeh.
• Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan.
• Pain. 2020 Jun 1; 161 (6): 1177-1190.

AbstractMorphine is a strong painkiller acting through mu-opioid receptor (MOR). Full-length 7-transmembrane (TM) variants of MOR share similar amino acid sequences of TM domains in rodents and humans; however, interspecies differences in N- and C-terminal amino acid sequences of MOR splice variants dramatically affect the downstream signaling. Thus, it is essential to develop a mouse model that expresses human MOR splice variants for opioid pharmacological studies. We generated 2 lines of fully humanized MOR mice (hMOR; mMOR mice), line #1 and #2. The novel murine model having human OPRM1 genes and human-specific variants was examined by reverse-transcription polymerase chain reaction and the MinION nanopore sequencing. The differences in the regional distribution of MOR between wild-type and humanized MOR mice brains were detected by RNAscope and radioligand binding assay. hMOR; mMOR mice were characterized in vivo using a tail-flick, charcoal meal, open field, tail suspension, naloxone precipitation tests, and rectal temperature measurement. The data indicated that wild-type and humanized MOR mice exhibited different pharmacology of morphine, including antinociception, tolerance, sedation, and withdrawal syndromes, suggesting the presence of species difference between mouse and human MORs. Therefore, hMOR; mMOR mice could serve as a novel mouse model for pharmacogenetic studies of opioids.

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