Chronic use of opioids results in tolerance to and dependance on the drug. One widely accepted mechanism for the cellular basis of tolerance is an uncoupling of receptor from effector so that greater receptor occupancy is required to obtain a given response. This mechanism has been proposed for opioid inhibition for calcium currents, adenylyl cyclase and transmitter release and the activation of potassium currents. Dependance is defined by a series of abnormal responses following removal of drug. Some signs and symptoms of dependance can be measured soon after removal of the drug, whereas others, such as the return to drug seeking behaviors and craving, persist for months or years. The expression of dependance is thought to result from the development of adaptive changes that occur in response to the continued presence of agonist. At the cellular level, the first adaptive response to be recognized was an upregulation of adenylyl cyclase. The adaptations in cellular and synaptic physiology mediated by this upregulation have, however, been largely unexplored. There are two goals of this proposal. The first is to define the events that lead to the activation and termination of opioid actions in locus coeruleus (LC). With a better understanding of the events between receptor and effector (potassium and calcium channels) the processors responsible for acute desensitization can be identified. The second goal is to study the regulation of dopamine cell activity in the ventral-segmental area (VTA) after chronic morphine treatment. This study will focus on the effects of the cAMP cascade on GABA synaptic potentials in slices. Both the onset and duration of altered synaptic regulation mediated by the cAMP cascade will be determined following chronic morphine treatment. The choice of these nuclei is based on extensive knowledge of opioid action at the cellular, biochemical and behavioral levels. The LC has been used as a model system for acute and chronic opioid actions. The VTA is thought to be important in the motivational aspects of drug abuse. Knowledge of alterations in regulation at the cellular and synaptic levels during acute and prolonged withdrawal from morphine will help in the development of more efficient protocols for the prevention of relapse to drug use.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Human Development Research Subcommittee (NIDA)
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Lin, Yu
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Oregon Health and Science University
Schools of Medicine
United States
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Arttamangkul, Seksiri; Heinz, Daniel A; Bunzow, James R et al. (2018) Cellular tolerance at the µ-opioid receptor is phosphorylation dependent. Elife 7:
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