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Intrathecal morphine induces myoclonic seizures in the rat
Abstract:
The development of myoclonic activity as a toxic effect of morphine application into the intrathecal space in rats is described. This syndrome resembled the human syndrome of action myoclonus by its spontaneous onset and its augmentation by initiation of movement or by an acoustic stimulus. It was not reversed or prevented by naloxone. This effect of morphine was associated with an increase in serotonergic activity in the spinal cord and was reduced by pretreatment with parachlorophenylalanine in doses which reduced spinal 5-HT by approximately 60%. The dose which produced this syndrome was about ten times higher than the analgesic dose applied by the same route. Other commonly used opiates such as: methadone (0.5-2 mg/kg), pethidine (2-10 mg/kg), fentanyl (2-10 micrograms/kg) and ketamine (2-10 mg/kg) did not produce myoclonic-like activity, but methadone and pethidine at the highest doses caused respiratory arrest. Fentanyl appeared to be the safest of the drugs tested since a relatively high dose, administered into the intrathecal space did not cause any side effects, while morphine was least safe of the five drugs since it produced myoclonic activity in addition to the widely documented respiratory depression. We suggest that the production of the myoclonic activity is mediated by spinal serotonergic systems.
Insights
Morphine administered intrathecally in rats caused myoclonic activity, a toxic effect not reversed by naloxone. This action myoclonus is linked to spinal serotonergic systems, suggesting a novel mechanism for morphine toxicity.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Intrathecal morphine administration can induce adverse effects.
- Action myoclonus is a neurological syndrome characterized by involuntary muscle jerks.
Purpose of the Study:
- To investigate the development of myoclonic activity following intrathecal morphine administration in rats.
- To explore the neurochemical mechanisms underlying morphine-induced myoclonus.
- To compare the safety profile of intrathecal morphine with other opioids and ketamine.
Main Methods:
- Intrathecal administration of morphine and other agents in rats.
- Observation and characterization of myoclonic activity.
- Assessment of naloxone's effect on myoclonus.
- Measurement of spinal 5-hydroxytryptamine (5-HT) levels.
- Pretreatment with parachlorophenylalanine (PCPA) to modulate 5-HT.
Main Results:
- Intrathecal morphine induced a myoclonic syndrome in rats, resembling human action myoclonus.
- This effect was not reversed by naloxone but was reduced by PCPA, indicating a role for spinal serotonergic systems.
- Morphine-induced myoclonus occurred at doses approximately ten times higher than analgesic doses.
- Methadone, pethidine, and ketamine did not produce myoclonic activity, though high doses of methadone and pethidine caused respiratory arrest.
- Fentanyl demonstrated a favorable safety profile at the tested intrathecal doses.
Conclusions:
- Spinal serotonergic systems likely mediate morphine-induced myoclonic activity.
- Intrathecal morphine poses a higher safety risk than fentanyl due to its potential to cause myoclonus and respiratory depression.
- The findings highlight a specific toxicological pathway for intrathecal morphine.