Project Details


Morphine and other opioids are widely used in clinical management of
severe pain. One problem of prolonged use of morphine is that tolerance
develops. Morphine exerts its effects mainly at the mu opioid receptors.
Development of morphine tolerance is a complex process, involving changes
at the cellular level and in neural circuitry. Despite numerous studies,
mechanisms for morphine tolerance are still not well-understood, partly
because there are no cellular models in which the mu receptor can be
manipulated to address specific questions. Recently a mu opioid receptor
has been molecularly cloned, thus making it possible for the first time
to generate such cellular models. This is the goal of the present
proposal. The underlying hypothesis for this investigation is that the development
of morphine tolerance at the cellular level results from specific
molecular events that are mediated through the mu opioid receptor. Two
mammalian cell lines, PC12 pheochromocytoma cells and Chinese hamster
ovary cells, will be used to stably express the mu receptor. Coupling of
the mu receptor to the cAMP pathway and ion channels will be determined
with acute opioid treatment. Then, development of morphine tolerance will
be studied by chronically exposing the cells to morphine and determining
the molecular events that underlie the changes during tolerance
development. Furthermore, the role of phosphorylation in regulating
receptor function will be studied by systematically mutating the
potential phosphorylation sites of protein kinases A and C, generating
cell lines that express the mutant receptors, and examining the effect
of these mutations on receptor function. These cells will also be
chronically exposed to morphine to determine the potential role of
receptor phosphorylation in tolerance development. These studies will provide important information as to the molecular
mechanisms of tolerance development through the mu opioid receptor. Such
information will contribute to our knowledge on how opioid drugs may act
at receptors and will provide a basis in designing strategies to
circumvent the problem of opioid tolerance in the clinical management of
Effective start/end date9/1/947/31/97


  • National Institutes of Health: $210,224.00
  • National Institutes of Health
  • National Institutes of Health: $193,321.00


  • Medicine(all)


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