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Modulation of NMDA receptor subunit mRNA in butorphanol-tolerant and -withdrawing rats
1Department of Neuroscience and Medical Research Center, College of Medicine, Ewha Womans University, Seoul, Korea.
Abstract:
The NMDA receptor has been implicated in opioid tolerance and withdrawal. The effects of continuous infusion of butorphanol on the modulation of NMDA receptor subunit NR1, NR2A, NR2B, and NR2C gene expression were investigated by using in situ hybridization technique. Continuous intracerebroventricular (i.c.v.) infusion with butorphanol (26 nmol/microl/h) resulted in significant modulations in the NRI, NR2A, and NR2B mRNA levels. The level of NR1 mRNA was significantly decreased in the cerebral cortex, thalamus, and CA1 area of hippocampus in butorphanol tolerant and withdrawal (7 h after stopping the infusion) rats. The NR2A mRNA was significantly decreased in the CA1 and CA3 of hippocampus in tolerant rats and increased in the cerebral cortex and dentate gyrus in butorphanol withdrawal rats. NR2B subunit mRNA was decreased in the cerebral cortex, caudate putamen, thalamus, CA3 of hippocampus in butorphanol withdrawal rats. No changes of NR1, NR2A, NR2C subunit mRNA in the cerebellar granule cell layer were observed in either butorphanol tolerant or withdrawal rats. Using quantitative ligand autoradiography, the binding of NMDA receptor ligand [3H]MK-801 was increased significantly in all brain regions except in the thalamus and hippocampus, at the 7 hr after stopping the butorphanol infusion. These results suggest that region-specific changes of NMDA receptor subunit mRNA (NR1 and NR2) as well as NMDA receptor binding ([3H]MK-801) are involved in the development of tolerance to and withdrawal from butorphanol.
Insights
Butorphanol alters NMDA receptor gene expression and binding in specific brain regions. These changes in NR1 and NR2 subunits are linked to opioid tolerance and withdrawal symptoms.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- The N-methyl-D-aspartate (NMDA) receptor is crucial in opioid tolerance and withdrawal.
- Butorphanol is an opioid agonist-antagonist with implications for these processes.
Purpose of the Study:
- To investigate the effects of continuous butorphanol infusion on NMDA receptor subunit gene expression.
- To determine the role of NMDA receptor modulation in butorphanol-induced tolerance and withdrawal.
Main Methods:
- In situ hybridization was used to measure NR1, NR2A, NR2B, and NR2C mRNA levels.
- Quantitative ligand autoradiography assessed NMDA receptor binding using [3H]MK-801.
Main Results:
- Butorphanol infusion significantly altered NR1, NR2A, and NR2B mRNA levels in a region-specific manner.
- NMDA receptor binding ([3H]MK-801) increased in most brain regions during withdrawal.
- No significant changes in cerebellar NR1, NR2A, or NR2C mRNA were observed.
Conclusions:
- Region-specific alterations in NMDA receptor subunit mRNA and binding are implicated in butorphanol tolerance and withdrawal.
- These findings highlight the NMDA receptor's role in opioid-related neuroadaptations.