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Blockade of morphine-induced hindlimb myoclonic seizures in mice by ketamine
Y Kolesnikov1, S Jain, R Wilson
1Department of Anesthesiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Abstract:
Morphine administration can lead to a variety of side-effects, including myoclonus. In an animal model, high morphine doses given intrathecally elicit hindlimb myoclonic seizures which are not influenced by traditional opioid receptor antagonists, such as naloxone. Ketamine prevents this seizure-like activity in a dose-dependent manner. The response is stereoselective, with S-ketamine far more potent than R-ketamine. A competitive NMDA antagonist, NPC17742, also prevents the seizures, although less potently than ketamine. Dextromethorphan has limited activity in this model, while haloperidol and pentothal are without any effect.
Insights
High morphine doses cause seizures in animals, but ketamine, particularly S-ketamine, effectively prevents this. NMDA receptor antagonists also show some effect, unlike opioid antagonists.
Area of Science:
- Neuroscience
- Pharmacology
- Anesthesiology
Background:
- Morphine, an opioid analgesic, can induce side effects like myoclonus.
- Intrathecal morphine in animal models can trigger hindlimb myoclonic seizures.
- Traditional opioid antagonists like naloxone do not affect morphine-induced seizures.
Purpose of the Study:
- To investigate the efficacy of ketamine and other agents in preventing morphine-induced myoclonic seizures.
- To explore the mechanism underlying morphine-induced seizures, focusing on NMDA receptor involvement.
Main Methods:
- Utilizing an animal model to induce myoclonic seizures via intrathecal morphine administration.
- Administering ketamine (S- and R-enantiomers), NPC17742 (NMDA antagonist), dextromethorphan, haloperidol, and pentothal to assess their effects.
- Evaluating the dose-dependent and stereoselective properties of ketamine's anticonvulsant activity.
Main Results:
- Ketamine demonstrated a dose-dependent and stereoselective prevention of morphine-induced seizures, with S-ketamine being more potent.
- A competitive NMDA antagonist, NPC17742, also showed efficacy, though less potent than ketamine.
- Dextromethorphan exhibited limited activity, while haloperidol and pentothal were ineffective.
Conclusions:
- Ketamine's anticonvulsant effect against morphine-induced seizures is likely mediated through NMDA receptor antagonism.
- The findings suggest a role for NMDA receptors in the pathophysiology of opioid-induced myoclonus.
- Ketamine represents a potential therapeutic agent for managing morphine-induced myoclonic side effects.