DEXTROROTATORY OPIOIDS AS PROBES FOR PCP RECEPTORS

Project: Research project

Description

Dextrorphan is the major metabolite 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. This relationship has
been established at the electrophysiological level where dextrorphan has
been shown, like PCP and ketamine, to be a potent antagonist of NMDA-
induced excitation in spinal cord neurons. At the behavioral level
dextrorphan shares discriminative stimulus properties with PCP suggesting a
common basis of action for these two compounds. Notwithstanding the
commonalities of action between dextrorphan and other noncompetitive
antagonists of NMDA receptors, the results of both radioligand binding and
electrophysiological experiments suggest that the mechanism of dextrorphan
interaction with the PCP recognition domain of the NMDA receptor is
distinctive. 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 the proposed
project is to elucidate the molecular mechanisms which underlie the unique
actions of dextrorphan. These studies will utilize [3H]dextrorphan as a
probe for PCP receptors. Investigation of association and dissociation
kinetics will be performed to delineate the mechanism of [3H]dextrorphan
binding to the PCP receptor in rat brain membranes. The distribution and
pharmacological signature of [3H]dextrorphan binding sites will be
determined in brain slices using quantitative receptor autoradiography. To
explore correlations between the potencies as anticonvulsants, the ability
of these ligands to suppress seizures evoked by kainic acid in the rat
prepiriform cortex will be evaluated. These results will establish the
functional consequences of ligand interaction with the dextrorphan binding
site in a region of the cerebral cortex. The potential for anatomically
distinct forms of the labeled receptor will be assessed through the
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 therapy of epilepsy, schizophrenia,
ischemic cell death and drug abuse.
StatusFinished
Effective start/end date7/1/913/31/01

Funding

  • National Institutes of Health: $116,881.00
  • National Institutes of Health
  • National Institutes of Health: $121,755.00
  • National Institutes of Health
  • National Institutes of Health: $148,600.00
  • National Institutes of Health: $112,323.00
  • National Institutes of Health

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Phencyclidine Receptors
Dextrorphan
Opioid Analgesics
N-Methyl-D-Aspartate Receptors
Dizocilpine Maleate
Dextromethorphan
Ketamine
Ion Channels
N-Methylaspartate
Benzomorphans
Antitussive Agents
Ligands
Kainic Acid
Brain
Morphinans
Autoradiography
Cerebral Cortex
Anticonvulsants
Substance-Related Disorders
Epilepsy