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Distribution of N-type Ca2+ channel binding sites in rabbit brain following central administration of omega-conotoxin
S L Whorlow1, R E Loiacono, J A Angus
1Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
Abstract:
Central administration of the N-type Ca2+ channel blocker omega-conotoxin GVIA in conscious rabbits has previously been shown to result in a slowly developing hypotensive and sympatholytic effect, with peak changes observed after 48 h. The aim of the current study was to examine the distribution of [125I] omega-conotoxin GVIA binding in rabbit brain alone or following a prior i.c.v. injection of omega-conotoxin GVIA to determine the site(s) of action of centrally administered omega-conotoxin GVIA. Brains were removed from rabbits 2 or 48 h after central administration of vehicle or non-labelled omega-conotoxin GVIA (30 pmol/kg, i.c.v.). Brain sections were then incubated with [125I] omega-conotoxin GVIA (50 pM) and the density of specific [125I] omega-conotoxin GVIA binding measured in dpm/mm2 was determined by quantitative receptor autoradiography. In the vehicle group, highest densities of [125I] omega-conotoxin GVIA binding sites (> 20 dpm/mm2) were detected in cortex, caudate, putamen, and the stratum oriens and stratum radiatum of the hippocampus. Prior (48 h) i.c.v. injection of omega-conotoxin GVIA resulted in a decrease in specific binding of [125I] omega-conotoxin GVIA, particularly in cortex and some portions of the caudate and hippocampus. Lesser effects were observed with a prior (2 h) i.c.v. injection of omega-conotoxin GVIA. Central administration of omega-conotoxin GVIA may be acting to disrupt neurotransmission in higher brain regions which may, in turn, affect cardiovascular control mechanisms in the rabbit.
Insights
Central administration of omega-conotoxin GVIA in rabbits causes hypotension by affecting N-type calcium channels in the brain. This study maps binding sites, revealing key areas like the cortex and hippocampus involved in its sympatholytic effects.
Area of Science:
- Neuroscience
- Pharmacology
- Cardiovascular Physiology
Background:
- Central administration of N-type Ca2+ channel blocker omega-conotoxin GVIA induces hypotension and sympatholysis in rabbits.
- Peak effects are observed 48 hours post-administration, suggesting a delayed mechanism of action.
Purpose of the Study:
- To investigate the distribution of [125I] omega-conotoxin GVIA binding sites in the rabbit brain.
- To identify the specific brain regions targeted by centrally administered omega-conotoxin GVIA.
- To correlate binding site distribution with the observed hypotensive and sympatholytic effects.
Main Methods:
- Quantitative receptor autoradiography was used to measure [125I] omega-conotoxin GVIA binding in rabbit brain sections.
- Brains were collected 2 or 48 hours after intracerebroventricular (i.c.v.) injection of vehicle or unlabeled omega-conotoxin GVIA.
- Specific binding densities were quantified in various brain regions.
Main Results:
- Highest binding densities of [125I] omega-conotoxin GVIA were found in the cortex, caudate, putamen, and hippocampus (stratum oriens and radiatum).
- Prior i.c.v. injection of omega-conotoxin GVIA significantly reduced [125I] binding in the cortex, caudate, and hippocampus, especially at 48 hours.
- A 2-hour pre-treatment showed less impact on binding compared to the 48-hour pre-treatment.
Conclusions:
- Central omega-conotoxin GVIA targets specific brain regions, including higher cortical and hippocampal areas.
- Disruption of neurotransmission in these regions likely underlies the observed cardiovascular effects.
- These findings elucidate the central mechanisms of omega-conotoxin GVIA's sympatholytic action in rabbits.