This is the fourth renewal (but third from my present post at the University of Minnesota), of my Career Research Scientist Award (K05 DA70554-27) which releases me from all the classroom teaching and most of the administrative duties at the University. The overall goal is to continue my long-standing research program in the molecular mechanisms of opioid actions and in the molecular basis of opioid tolerance. The current proposal is to test the hypothesis that the alteration in mu-opioid receptor synthesis and regulation is related to the mechanism of morphine action and morphine tolerance. To achieve this goal, we plan to carry out two independent but related studies: 1) to determine the regulation of mu-opioid receptor gene expression which controls the synthesis of receptors in specific cells. We hypothesize that the difference in spatial and temporal expression of mu-opioid receptor gene are caused by (or resultant of) characteristic interactions between cis- and transregulatory elements that exist in different cells (tissues) at different times. Therefore, we plan to define these elements using in vitro and in vivo models, 2) to determine the molecular mechanism of mu-opioid receptor regulation by a chemical modification (i.e., phosphorylation) and determine its possible relationship to morphine tolerance. In these studies we aim to elucidate the exact role of receptor phosphorylation/ dephosphorylation on cellular adaptation of chronic opioid treatment (i.e., tolerance). We also plan to pinpoint the exact phosphorylation sites of cloned opioid receptors which are involved in receptor desensitization as well as to determine the protein kinases (or other protein factors) that are involved in this process.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Award (K05)
Project #
5K05DA070554-28
Application #
6174593
Study Section
Special Emphasis Panel (ZDA1-MXS-M (12))
Program Officer
Koustova, Elena
Project Start
1989-08-01
Project End
2004-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
28
Fiscal Year
2000
Total Cost
$123,930
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Wagley, Yadav; Hwang, Cheol Kyu; Lin, Hong-Yiou et al. (2013) Inhibition of c-Jun NH2-terminal kinase stimulates mu opioid receptor expression via p38 MAPK-mediated nuclear NF-?B activation in neuronal and non-neuronal cells. Biochim Biophys Acta 1833:1476-88
Song, Kyu Young; Choi, Hack Sun; Law, Ping-Yee et al. (2012) Post-transcriptional regulation of mu-opioid receptor: role of the RNA-binding proteins heterogeneous nuclear ribonucleoprotein H1 and F. Cell Mol Life Sci 69:599-610
Hwang, Cheol Kyu; Wagley, Yadav; Law, Ping-Yee et al. (2012) MicroRNAs in opioid pharmacology. J Neuroimmune Pharmacol 7:808-19
Zheng, Hui; Chu, Ji; Zhang, Yuhan et al. (2011) Modulating micro-opioid receptor phosphorylation switches agonist-dependent signaling as reflected in PKCepsilon activation and dendritic spine stability. J Biol Chem 286:12724-33
Kim, Do Kyung; Hwang, Cheol Kyu; Wagley, Yadav et al. (2011) p38 mitogen-activated protein kinase and PI3-kinase are involved in up-regulation of mu opioid receptor transcription induced by cycloheximide. J Neurochem 116:1077-87
Wei, Li-Na; Loh, Horace H (2011) Transcriptional and epigenetic regulation of opioid receptor genes: present and future. Annu Rev Pharmacol Toxicol 51:75-97
Chu, Ji; Zheng, Hui; Zhang, Yuhan et al. (2010) Agonist-dependent mu-opioid receptor signaling can lead to heterologous desensitization. Cell Signal 22:684-96
Song, Kyu Young; Kim, Chun Sung; Hwang, Cheol Kyu et al. (2010) uAUG-mediated translational initiations are responsible for human mu opioid receptor gene expression. J Cell Mol Med 14:1113-24
Tao, Pao-Luh; Law, Ping-Yee; Loh, Horace H (2010) Search for the ""ideal analgesic"" in pain treatment by engineering the mu-opioid receptor. IUBMB Life 62:103-11
Zheng, Hui; Zeng, Yan; Chu, Ji et al. (2010) Modulations of NeuroD activity contribute to the differential effects of morphine and fentanyl on dendritic spine stability. J Neurosci 30:8102-10

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