MOLECULAR CHARACTERIZATION OF KAPPA RECEPTOR SUBTYPES

Project: Research project

Project Details

Description

The goals of the proposed studies are to elucidate the molecular
properties and mechanisms of actions of the kappa 1 (U-69, 593-sensitive)
and kappa 2 (U-69,593-insensitive) subtypes of the kappa receptor and
provide information about the molecular bases of kappa receptor
heterogeneity. Kappa receptors mediate the physiological actions of
dynorphin-related peptides and the antinociceptive and sedative actions
of ketocyclazocine-like opioids. The proposed research will test the
hypotheses that kappa 1 and kappa 2 receptor subtypes mediate excitatory
and inhibitory actions of kappa receptor ligands upon neurons in analogy
to the M1 and M2 subtypes of the muscarinic receptor. Specifically,
experiments are proposed to characterize pharmacologically kappa 1 and
kappa 2 opioid receptors of guinea pig and rat brain, determine their
localization throughout the brain and upon specific neuronal elements,
characterize electrophysiologically the functions which they mediate, and
construct anti-idiotypic antibodies against them. Detailed
pharmacological analyses using in vitro receptor assays together with
electrical recording methods will be used to determine the
electrophysiological responses associated with kappa 1 and kappa 2
receptor activation in cultures of embryonic rat striatal and hippocampal
neurons. Striatal neurons are particularly suitable because they have
been shown to have both kappa 1 and kappa 2 receptor subtypes, whereas
rat hippocampal neurons provide a pure source of kappa 2 receptors.
Quantitative in vitro autoradiography at the level of the light
microscope will be used together with selective neurotoxins to determine
upon which neuronal elements kappa 1 and kappa 2 receptors reside in
adult rat brain. Monoclonal anti-idiotypic antibodies will be generated
for use as tools in kappa receptor physiology and localization.
Specifically, the antibodies are important for 1) the determination of
regions of homology in the subtypes, 2) determination of the
neuroanatomical localization of the kappa 1 and kappa 2 receptors at a
high level of resolution, and 3) definitive identification of the
functions associated with each of the receptor subtypes as measured
electrophysiologically. The overall significance of the proposed
research lies in its ability to elucidate the molecular basis of kappa
receptor heterogeneity and provide information about kappa 1 and kappa 2
receptor function and localization. These studies are expected to
contribute significantly to our understanding of neuronal specialization
in the opioid system, of how the brain works with regard to pain
perception, and how, on the molecular level, opiates exert their
characteristic effects including tolerance, dependence, and addiction.
StatusFinished
Effective start/end date4/1/893/31/92

Funding

  • National Institutes of Health

ASJC

  • Medicine(all)
  • Biological Psychiatry
  • Cellular and Molecular Neuroscience
  • Cognitive Neuroscience
  • Developmental Neuroscience
  • Pharmacology

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