| 描述: | 博士
指導教授：莊健盈
指導教授：葉修華
指導教授：羅浩
委員：王昀
委員：劉景平
委員：吳育瑋
委員：林惠菁
Opioid analgesics are widely used and are effective for pain relief. Clinically used opioids, such as morphine, produce both potent analgesia and several side effects by acting on the mu opioid receptor (MOR). The differences in N- and C-terminal amino acid sequences of MOR splice variants among species may cause diversity in the pharmacological phenomenon of opioids. Therefore, we generated a humanized mouse model expressing various human MOR splicing variants for preclinical studies of opioids. A novel murine model, the human OPRM1 (hOPRM1) mouse with human OPRM1 genes and human-specific variants, was examined by reverse transcription polymerase chain reaction (RT-PCR) and MinION nanopore sequencing. The differences in the regional distribution of MOR between wild-type (WT) and hOPRM1 mouse brains were detected by RNAscope and radioligand binding assays. Results of the tail-flick test showed that morphine exerted potent antinociception in hOPRM1 mice. Another opioid drug, TRV130, exerted more potent analgesia for neuropathic and inflammatory pain in hOPRM1 mice than in WT mice. All pharmacological effects of morphine were detected by the following tests: the tail-flick, charcoal meal, open field, tail suspension, naloxone precipitation tests, as well as rectal temperature measurements. The data indicated that WT and hOPRM1 mice exhibited different pharmacology of morphine, including tolerance, sedation, hypothermia, and withdrawal syndromes in hOPRM1 mice. Furthermore, morphine-induced sedation and hypothermia did not correlate with morphine-induced analgesia. Taken together, the humanized MOR mice provide useful information regarding the pharmacology of opioids through human MORs. |
