The molecular mechanism for morphine tolerance has not been firmly established yet. The current model of [j-opioid receptor (MOR) desensitization via the &-Arrestin pathway cannot account for the numerous observations that other neurotransmitter receptor activities, such as NMDA, could contribute to morphine tolerance. The activity of other opioid receptors, such as the 6-opioid receptor (DOR), could be implicated in morphine tolerance development also. Since morphine can activate and desensitize DOR during prolonged treatment, our working hypothesis is that the post-signaling events occurring within the DOR-containing neurons during morphine treatment contribute to tolerance development. Our working hypothesis also is that morphine has post-signaling events distinct from those of other opioid agonists. In order to demonstrate these hypotheses, agonist-dependent signaling events will be established for morphine activation of DOR. In our studies with MOR signaling, we have demonstrated that morphine differs from other agonists in its pathway to activate ERK1/2. Agonists such as etorphine activate ERK1/2 via the B-Arrestin-dependent pathway, while morphine activates ERK1/2 via the PKC-dependent pathway. This divergent activation results in differential translocation of the activated ERK1/2 and the transcripts produced. Therefore, the signaling pathway and the post-signaling events of morphine in cell models expressing DOR will be established. The possible involvement of the PKC-dependent pathway on morphine-mediated DOR activation of ERK1/2 will be studied. The specific PKC subtypes involved will be defined. The reasons for the differences among agonists in selecting a pathway will be investigated by monitoring protein-protein interactions using a novel protease assay system. Parallel studies will be conducted with primary neuronal cultures. The blockade of specific PKC subtypes in DOR-expressing neurons on in vivo morphine tolerance development will be explored. By selectively inactivating the morphine signaling pathway, and subsequently its post-signaling events in DOR-containing neurons, possible blockade of morphine tolerance without altering morphine activities in MOR containing neuron could be accomplished.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA011806-15
Application #
8378935
Study Section
Special Emphasis Panel (ZDA1-RXL-E)
Project Start
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
15
Fiscal Year
2012
Total Cost
$187,151
Indirect Cost
$61,569
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Kibaly, Cherkaouia; Kam, Angel Y F; Loh, Horace H et al. (2016) Naltrexone Facilitates Learning and Delays Extinction by Increasing AMPA Receptor Phosphorylation and Membrane Insertion. Biol Psychiatry 79:906-16
Banerjee, S; Sindberg, G; Wang, F et al. (2016) Opioid-induced gut microbial disruption and bile dysregulation leads to gut barrier compromise and sustained systemic inflammation. Mucosal Immunol 9:1418-1428
Hwang, Cheol Kyu; Wagley, Yadav; Law, Ping-Yee et al. (2015) Analysis of epigenetic mechanisms regulating opioid receptor gene transcription. Methods Mol Biol 1230:39-51
Wang, Yan; Ge, Yan-Hui; Wang, Yan-Xia et al. (2015) Modulation of mTOR Activity by μ-Opioid Receptor is Dependent upon the Association of Receptor and FK506-Binding Protein 12. CNS Neurosci Ther 21:591-8
Kotecki, Lydia; Hearing, Matthew; McCall, Nora M et al. (2015) GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner. J Neurosci 35:7131-42
Banerjee, Santanu; Ninkovic, Jana; Meng, Jingjing et al. (2015) Morphine compromises bronchial epithelial TLR2/IL17R signaling crosstalk, necessary for lung IL17 homeostasis. Sci Rep 5:11384
Meng, Jingjing; Banerjee, Santanu; Li, Dan et al. (2015) Opioid Exacerbation of Gram-positive sepsis, induced by Gut Microbial Modulation, is Rescued by IL-17A Neutralization. Sci Rep 5:10918
Wang, Yan; Wang, Yan-Xia; Liu, Ting et al. (2015) μ-Opioid receptor attenuates Aβ oligomers-induced neurotoxicity through mTOR signaling. CNS Neurosci Ther 21:8-14
Yan, Ying-Hui; Wang, Yan; Zhao, Lan-Xue et al. (2014) Role of FK506 binding protein 12 in morphine-induced μ-opioid receptor internalization and desensitization. Neurosci Lett 566:231-5
Koodie, Lisa; Yuan, Hongyan; Pumper, Jeffery A et al. (2014) Morphine inhibits migration of tumor-infiltrating leukocytes and suppresses angiogenesis associated with tumor growth in mice. Am J Pathol 184:1073-84

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