Chronic use of morphine results in tolerance to and dependence on the drug. One mechanism underlying cellular tolerance is an uncoupling of the opioid receptor from effects such that greater receptor occupancy is required to obtain a given response. This uncoupling mechanism has been studied using effectors that include; potassium and calcium conductances and the inhibition of adenylyl cyclase. A similar phenomenon is observed with acute opioid desensitization. Acute desensitization is thought to involve at least two linked processes, receptor uncoupling through an arresting dependent mechanism and removal of receptors from the plasma membrane through an internalization mechanism. Unlike more protracted forms of tolerance, acute desensitization is reversible within minutes and therefore easier to study in vitro. One goal of this proposal is to define the events that mediate the initiation and recovery from acute opioid desensitization. This goal has two parts, one is to characterize acute desensitization and determine the role of receptor internalization in that process. Given that receptor trafficking is an important form of receptor regulation, the second goal is to characterize how chronic morphine treatment alters desensitization and internalization of the opioid receptor. With a better understanding of the events that mediate desensitization and internalization the processes leading to long term tolerance may be more easily identified. The second goal is to identify post-synaptic cellular adaptations to chronic opioid treatment. These adaptations oppose the initial effect of opioid such that normal function is attained even in the continued presence of morphine. Thus adaptive mechanisms underlie an important form of tolerance. Two cell types will be examined the neurons in the locus coeruleus and interneurons of the VTA. There is an extensive knowledge of opioid actions in these areas, however, the identification and characterization of a post-synaptic adaptive mechanism studied in isolation has yet to be presented. Knowledge of alterations in regulation of ion channels during withdrawal form morphine may help in the development of more efficient protocols for the prevention of relapse to drug use.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA008163-10
Application #
6470458
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (02))
Program Officer
Lin, Yu
Project Start
1993-04-01
Project End
2007-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
10
Fiscal Year
2002
Total Cost
$276,500
Indirect Cost
Name
Oregon Health and Science University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Arttamangkul, Seksiri; Heinz, Daniel A; Bunzow, James R et al. (2018) Cellular tolerance at the µ-opioid receptor is phosphorylation dependent. Elife 7:
Levitt, Erica S; Williams, John T (2018) Desensitization and Tolerance of Mu Opioid Receptors on Pontine Kölliker-Fuse Neurons. Mol Pharmacol 93:8-13
Hunnicutt, Barbara J; Jongbloets, Bart C; Birdsong, William T et al. (2016) A comprehensive excitatory input map of the striatum reveals novel functional organization. Elife 5:
Arttamangkul, Seksiri; Birdsong, William; Williams, John T (2015) Does PKC activation increase the homologous desensitization of ? opioid receptors? Br J Pharmacol 172:583-92
Levitt, Erica S; Abdala, Ana P; Paton, Julian F R et al. (2015) ? opioid receptor activation hyperpolarizes respiratory-controlling Kölliker-Fuse neurons and suppresses post-inspiratory drive. J Physiol 593:4453-69
Birdsong, William T; Arttamangkul, Seksiri; Bunzow, James R et al. (2015) Agonist Binding and Desensitization of the ?-Opioid Receptor Is Modulated by Phosphorylation of the C-Terminal Tail Domain. Mol Pharmacol 88:816-24
Williams, John T (2014) Desensitization of functional µ-opioid receptors increases agonist off-rate. Mol Pharmacol 86:52-61
Birdsong, William T; Arttamangkul, Seksiri; Clark, Mary J et al. (2013) Increased agonist affinity at the ?-opioid receptor induced by prolonged agonist exposure. J Neurosci 33:4118-27
Banghart, Matthew R; Williams, John T; Shah, Ruchir C et al. (2013) Caged naloxone reveals opioid signaling deactivation kinetics. Mol Pharmacol 84:687-95
Arttamangkul, Seksiri; Lau, Elaine K; Lu, Hsin-Wei et al. (2012) Desensitization and trafficking of ýý-opioid receptors in locus ceruleus neurons: modulation by kinases. Mol Pharmacol 81:348-55

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