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Effect of narcotics on monoamine oxidase activity of mouse brain
Abstract:
The effect of morphine, levorphanol and methadone on the monoamine oxidase (MAO) activity of mouse brain was studied. Both methadone and levorphanol produced a concentration-dependent inhibition of whole brain mitochondrial MAO in vitro with an IC50 of approximately 7.4 x 10(-4) for levorphanol and 2.5 x 10(-6)M for methadone. Methadone also produced a 60% inhibition of the MAO activity of the hippocampus, a 32% inhibition of the striatal and hypothalamic enzyme, a 30% inhibition of liver, and a 20 and 23% inhibition of the cerebral cortex and cerebellum, respectively. Naloxone did not antagonize this effect of methadone. In contrast, morphine had little effect in vitro except at very high concentrations where it was inhibitory. This was not linear with concentration and no IC50 could be estimated. This would imply that the inhibition by morphine is non-specific. When acutely administered to mice, morphine and methadone, again differed. Methadone produced a slight but significant inhibition of whole brain MAO and a 34% inhibition of the striatal enzyme. Morphine, on the other hand, produced a marked enhancement in the activity of the striatal enzyme. Since this action could not be demonstrated in vitro, it would suggest that the in vivo effect of morphine is indirect resulting from an alteration of some other modulating system.
Insights
Methadone and levorphanol inhibit monoamine oxidase (MAO) in mouse brains, while morphine shows minimal in vitro effects but enhances MAO activity in vivo, suggesting indirect action.
Area of Science:
- Neuropharmacology
- Enzymology
Background:
- Monoamine oxidase (MAO) enzymes are crucial for neurotransmitter metabolism.
- Opioids like morphine, levorphanol, and methadone interact with the central nervous system.
- Understanding their effects on MAO activity is key to elucidating their mechanisms of action.
Purpose of the Study:
- To investigate the in vitro and in vivo effects of morphine, levorphanol, and methadone on mouse brain monoamine oxidase (MAO) activity.
- To compare the direct enzymatic inhibition versus indirect modulation of MAO by these opioids.
Main Methods:
- In vitro enzyme inhibition assays using mouse brain mitochondria.
- In vivo administration of drugs to mice followed by MAO activity measurements in various brain regions.
- Concentration-dependent inhibition studies to determine IC50 values.
Main Results:
- Methadone and levorphanol demonstrated concentration-dependent inhibition of whole brain MAO in vitro.
- Methadone inhibited MAO in various brain regions and liver, with naloxone not affecting this inhibition.
- Morphine showed minimal in vitro MAO inhibition, but significantly enhanced striatal MAO activity in vivo, suggesting an indirect mechanism.
Conclusions:
- Levorphanol and methadone directly inhibit MAO activity in a concentration-dependent manner.
- Morphine's in vivo effect on MAO appears indirect, possibly mediated by other neurochemical systems.
- These findings differentiate the neurochemical actions of these opioids on MAO, impacting their pharmacological profiles.