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Toxic interaction between narcotic analgesics and inhibitors of catechol-O-methyltransferase
Abstract:
A lethal synergism between morphine and tropolone, an inhibitor of catechol-O-methyltransferase, was previously noted in adult male Holtzman rats. The present research demonstrates that this phenomenon generalizes across factors of sex, age, strain (Sprague--Dawley, Wistar) and species (Swiss albino mice). Acute toxicity was also significantly increased (1.5--1.9 times) in the case of codeine, methadone, meperidine and levorphanol, but to a lesser extent than for morphine (4.0 times) in the S-D strain. Another COMT inhibitor, 3,5-dihydroxy-4-methoxybenzoic acid, interacted with morphine in S-D rats to an equal degree as did tropolone. Post-treatment with 1 mg/kg of naloxone in rats or naltrexone in mice reduced the high lethality associated with morphine plus tropolone. There was a pronounced lowering of whole brain norepinephrine (NE) level after morphine plus tropolone in Wistar rats with doses of each component that alone caused no change in NE. Brain dopamine (DA) was elevated by tropolone and by its combination with morphine. Each drug alone caused slight lowering of brain serotonin. Enhancement by tropolone of the toxicity of (+)-amphetamine in mice and rats was of similar magnitude as for morphine. The possible role of brain NE and/or DA in the sensitivity to acute toxic effects of opioids in rodents is suggested by these data, as well as a parallel in this regard with amphetamine-type stimulants.
Insights
Lethal drug interactions between morphine and COMT inhibitors like tropolone are confirmed across diverse rodents. This synergism, affecting opioid toxicity, involves changes in brain norepinephrine and dopamine levels.
Area of Science:
- Pharmacology
- Neuroscience
- Toxicology
Background:
- A previously observed lethal synergism between morphine and tropolone (a catechol-O-methyltransferase inhibitor) in male rats.
- The need to understand if this interaction extends to other populations and opioid analgesics.
Purpose of the Study:
- To determine if the lethal synergism between morphine and tropolone is generalizable across sex, age, rat strains, and species.
- To investigate the effect of tropolone on the acute toxicity of other opioids and amphetamine.
- To explore the role of catecholamines in the observed toxicological interactions.
Main Methods:
- Administered morphine and tropolone to various rodent models (rats: Holtzman, Sprague-Dawley, Wistar; mice: Swiss albino) across different sexes and ages.
- Assessed acute toxicity of morphine, codeine, methadone, meperidine, levorphanol, and amphetamine in combination with tropolone or another COMT inhibitor.
- Measured whole brain norepinephrine, dopamine, and serotonin levels following drug administration.
- Utilized opioid antagonists (naloxone, naltrexone) to counteract lethality.
Main Results:
- The lethal synergism between morphine and tropolone was confirmed across sexes, ages, strains (Sprague-Dawley, Wistar), and species (mice).
- Other opioids (codeine, methadone, meperidine, levorphanol) showed increased acute toxicity with tropolone, though less than morphine.
- Morphine-tropolone combination significantly altered brain norepinephrine and dopamine levels, while tropolone alone elevated dopamine.
- Opioid antagonists reduced the lethality of the morphine-tropolone combination.
- Tropolone enhanced the toxicity of (+)-amphetamine similarly to morphine.
Conclusions:
- The lethal synergism between morphine and COMT inhibitors is a robust phenomenon in rodents, extending beyond the initially studied group.
- Brain norepinephrine and/or dopamine may play a critical role in the acute toxicity of opioids, paralleling effects seen with amphetamine-type stimulants.
- These findings highlight potential drug-drug interaction risks and suggest a common neurochemical pathway for opioid and stimulant toxicity.