NEURO-ONCOGENESIS &ENDOGENOUS OPIOID SYSTEMS

Project: Research project

Project Details

Description

Our laboratory has made the initial observations suggesting that
endogenous neuropeptides are related to neuro-oncogenicity, and
that alterations of endogenous opioid/opioid receptor interactions
influence the course of neoplasia (Science 221:671, 1983). During
the first 2 years of this grant, we have carefully defined the role
of endogenous opioid systems in neural cancer. A major discovery
was that endogenous opioids and opioid receptors are present in
all types of human and animal tumors, neural and non-neural in
origin. Our hypothesis is that endogenous opioids serve to
regulate neoplasia through interaction with opioid receptors
associated with tumor cells; this may reflect an autocrine
mechanism. In this grant proposal, we continue to explore our
thesis with a rigorously-defined murine neuroblastoma model.
Prototypic opioids related to growth will be identified through
drug displacement studies, and structure-function experiments in
tissue culture. Binding assays will be used to establish
opioid/receptor interaction, and will include assessment of
saturability, binding affinity and capacity. Information as to
precursors of growth-related opioids will be gained by
immunocytochemical procedures. In vitro investigations will be
correlated with physiological/pharmacological responsiveness to
opioids in mice with transplanted neuroblastoma. The cellular
mechanism of neuropeptide regulation will be studied
biochemically and structurally, by opioid transport experiments
using opioids conjugated to gold and examined by electron
microscopy, and with flow cytometry. Finally, the opioid
receptor associated with cell growth will be isolated and
identified. Receptor characteristics including size and subunit
composition, peptide maps, and binding function as studied by
reconstitution experiments, will be explored. Receptors will be
quantitated by immunodot assays, and receptor distribution
assessed by immunocytochemistry and immunoelectron
microscopy. Our research efforts will contribute to
comprehending the etiology and pathogenesis of neural neoplasia,
and will provide strategies for prevention and therapeutic
intervention of neuro-oncogenesis. This research is part of a
long-range program in cellular and molecular neurobiology which
seeks to understand the fundamental principles underlying normal
growth and abnormal growth of the nervous system.
StatusFinished
Effective start/end date4/1/843/31/92

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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