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Tolerance to methadone lethality and microsomal enzyme induction in mice tolerant to and dependent on morphine
Abstract:
In an attempt to explain a loss of cross-tolerance between morphine and methadone and an increased tolerance to methadone lethality in morphine-dependent mice administered methadone orally for six days, the possibility that methadone was stimulating its own metabolism was investigated. It was found that methadone did enhance its own metabolism two-fold. This increase in activity correlated with the development of tolerance to the lethal effects of methadone as measured by an elevation of the oral methadone LD50. Furthermore, SKF-525A, a potent microsomal inhibitor, abolished this tolerance. The intracerbroventricular methadone LD50 was not altered by six days administration of oral methadone, suggesting that the tolerance observed was dispositional in nature.
Insights
Methadone was found to double its own metabolism in mice, leading to increased tolerance to its lethal effects. This self-induced metabolic enhancement, a dispositional tolerance, was reversed by a microsomal inhibitor.
Area of Science:
- Pharmacology
- Toxicology
- Drug Metabolism
Background:
- Cross-tolerance between morphine and methadone can be lost.
- Increased tolerance to methadone lethality is observed in morphine-dependent mice.
- The mechanism behind this tolerance requires investigation.
Purpose of the Study:
- To investigate if methadone stimulates its own metabolism.
- To correlate metabolic enhancement with tolerance to methadone's lethal effects.
- To determine the nature of methadone tolerance (dispositional vs. central).
Main Methods:
- Oral administration of methadone to morphine-dependent mice for six days.
- Measurement of methadone metabolism enhancement (two-fold increase).
- Determination of oral and intracerebroventricular methadone LD50 (lethal dose, 50%).
- Administration of SKF-525A (microsomal inhibitor) to assess its effect on tolerance.
Main Results:
- Methadone significantly enhanced its own metabolism by two-fold.
- This metabolic enhancement correlated with an elevated oral methadone LD50, indicating tolerance.
- The microsomal inhibitor SKF-525A abolished the observed tolerance.
- Intracerebroventricular methadone LD50 remained unchanged, suggesting peripheral mechanisms.
Conclusions:
- Methadone induces its own metabolism, contributing to tolerance.
- The observed tolerance to methadone lethality is primarily dispositional (related to drug processing).
- Microsomal enzyme induction plays a key role in methadone's self-metabolism and tolerance development.