A close relationship between desensitization and internalization of mu opioid receptors has been proposed based on differential actions of series of agonists. A wide variety of opioids that have dramatically different pharmacological properties are used in the clinic for the treatment of various forms of pain as well as the managment of drug addiction. Agonists that are commonly administered on a chronic basis are morphine, methadone and buprenorphine. Morphine and buprenorphine do not induce marked acute desensitization or trafficking of receptors, but, methadone is efficient at causing both processes. The role that desensitization and internalization have in the development of tolerance and dependence to opioids has been a controversial subject and has been studied in a variety of model systems. There has, however, been only limited study on potential differences in the development and expression of tolerance that result from the chronic treatment of animals with these three commonly used opioid agonists. The goal of this work is to examine both desensitization and internlaization of receptors in neurons after treating animals chronically with each of these agonists. Opioid receptor desensitization and internalization are highly regulated processes in neurons and the primary hypothesis of this proposal is that these processes are altered in an agonist specific way following chronic treatment.
The first aim will examine tolerance and the recovery from acute desensitization in animals (rats) treated chronically with morphine, methadone and buprenorphine.
The second aim will examine how receptor internalization induced by a desensitizing concentration of agonist is altered following the chronic treatment of animals (transgenic mice) with each of the three agonists.
The third aim will test the hypothesis that receptor desensitization and internlaization are separate events and that receptor internalization and functional reinsertion to the plasma membrane is dramatically altered by chronic agonist treatment. By gaining knowledge of the processes that are selectively affected by some agonists and not others, the mechanisms underlying the development of tolerance and dependence may be identified and applied to more effective treatment of chronic pain and addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA008163-19
Application #
8115852
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Sorensen, Roger
Project Start
1993-04-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
19
Fiscal Year
2011
Total Cost
$253,624
Indirect Cost
Name
Oregon Health and Science University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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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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