1. Morphine produces potent antinociception, sedation, and hypothermia in humanized mice expressing human mu-opioid receptor splice variants.
- Author
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Yi-Han Huang, Yu-Wei Wu, Jian-Ying Chuang, Yung-Chiao Chang, Hsiao-Fu Chang, Pao-Luh Tao, Horace H. Loh, Shiu-Hwa Yeh, Huang, Yi-Han, Wu, Yu-Wei, Chuang, Jian-Ying, Chang, Yung-Chiao, Chang, Hsiao-Fu, Tao, Pao-Luh, Loh, Horace H, and Yeh, Shiu-Hwa
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AMINO acid sequence , *RADIOLIGAND assay , *MORPHINE , *MICE , *POLYMERASE chain reaction , *NARCOTICS , *RESEARCH , *DRUG tolerance , *ANALGESICS , *ANIMAL experimentation , *RESEARCH methodology , *CELL receptors , *MEDICAL cooperation , *EVALUATION research , *COMPARATIVE studies , *HYPOTHERMIA , *AMINO acids , *PHARMACODYNAMICS - Abstract
Morphine 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. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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