Morphine produces potent antinociception, sedation, and hypothermia in humanized mice expressing human mu-opioid receptor splice variants. Issue 6 (June 2020)

• Record Type: Journal Article
• Authors: Huang, Yi-Han; Wu, Yu-Wei; Chuang, Jian-Ying; Chang, Yung-Chiao; Chang, Hsiao-Fu; Tao, Pao-Luh; Loh, Horace H.; Yeh, Shiu-Hwa
• Is Part Of: Pain. Volume 161:Issue 6(2020)
• Publication Date: 2020-06
• Subjects: Morphine -- Mu-opioid receptor -- Humanized mice -- Antinociceptive effect -- Side effect -- Alternatively spliced variants; Pain -- Periodicals; Douleur -- Périodiques; Anesthésie -- Périodiques; Pain; Electronic journals; Periodicals; Electronic journals; 616.0472
• DOI: 10.1097/j.pain.0000000000001823
• Languages: English
• ISSNs: 0304-3959

Abstract

Abstract : 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 : Supplemental Digital Content is Available in the Text.Morphine induces potent antinociception and severe constipation, sedation, and hypothermia; however, it exhibits minor antinociceptive tolerance in fully humanized mu-opioid receptor mouse model.