DEXTROROTATORY OPIOIDS AS PROBES FOR PCP RECEPTORS

Project: Research project

Description

This is a request for an ADAMHA Research Scientist Development Award
(RSDA) that will enable the applicant to engage in research, on
essentially a full-time basis, for an extended period. By relieving the
applicant from a particularly heavy teaching load which currently
occupies approximately 40% of his time, the RSDA will allow the applicant
to both focus on existing research activities and to develop competence
in new areas for future research initiatives. Ongoing research (DA 07218) in the applicant's laboratory is focused on
the mechanisms underlying dextrorotatory opioid interaction with the NMDA
receptor. Dextrorphan is the major metabolite of dextromethorphan, a
clinically used over-the-counter antitussive. Dextrorphan and related
dextrorotatory morphinans and benzomorphans are similar to the
dissociative anesthetics phencyclidine (PCP) and ketamine in that they
act as selective noncompetitive antagonists of the NMDA receptor.
Dextrorphan is unique in that it does not exhibit the striking use-
dependence that is characteristic of the NMDA receptor blockade produced
by PCP, ketamine and MK-801. The focus of ongoing research is to
elucidate the molecular mechanisms which underlie the unique actions of
dextrorphan. These studies utilize [H]dextrorphan as a probe for PCP
receptors. Investigation of association and dissociation kinetics are
being performed to delineate the mechanism of [H]dextrorphan binding to
the PCP receptor in rat brain membranes. The distribution and
pharmacological signature of [H]dextrorphan binding sites will be
determined in brain slices using pharmacological signature of
[H]dextrorphan binding sites will be determined in brain slices using
quantitative receptor autoradiography. The potential for anatomically
distinct forms of the labeled receptor is being assessed through
investigation of biochemical and physiological regulation of the
receptor. A further characterization of dextrorphan as a probe for the
PCP receptor may provide useful insights into the mechanisms underlying
and consequences of PCP and dextromethorphan abuse. An additional project (DA 05195, J.V. Aldrich, PI) in which the applicant
is involved is focused on the characterization of synthetic dynorphin
analogs as kappa opioid receptor antagonists. The goal of the applicant during the RSDA funding period is to continue
to develop as a research scientist in the area of molecular pharmacology
of abused drugs. Scientific growth will be enhanced through
collaboration with a molecular biologist and an extended visit to the
laboratory of a molecular pharmacologist. Specific training will be
obtained in several areas of molecular biology.
StatusFinished
Effective start/end date6/1/945/31/99

Funding

  • National Institutes of Health: $76,033.00
  • National Institutes of Health: $79,673.00
  • National Institutes of Health: $13,987.00
  • National Institutes of Health: $83,067.00

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Phencyclidine Receptors
Dextrorphan
Opioid Analgesics
Research
Dextromethorphan
N-Methyl-D-Aspartate Receptors
Ketamine
Phencyclidine Abuse
Morphinans
Brain
Benzomorphans
Binding Sites
Dissociative Disorders
Pharmacology
Antitussive Agents
Phencyclidine
kappa Opioid Receptor
Dizocilpine Maleate
Narcotic Antagonists
Autoradiography