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NEUROSURGICAL ANESTHESIA

Mechanisms of Morphine Enhancement of Spontaneous Seizure Activity

Ehsan Saboory, PhD^*, Miron Derchansky, PhD^*, Mohammed Ismaili, PhD^*, Shokrollah S. Jahromi, PhD^*, Richard Brull, MD, FRCPC, Peter L. Carlen, MD, FRCPC^*, and Hossam El Beheiry, MBBCh, PhD, FRCPC^*

From the *Toronto Western Research Institute, Departments of Physiology, Anesthesia and Pain Management, and Medicine (Neurology), University of Toronto, University Health Network, Toronto, Ontario, Canada.

Address correspondence and reprint requests to Hossam El Beheiry, MBBCh, PhD, FRCPC, Department of Anesthesia and Pain Management, Toronto Western Hospital, University Health Network, 399 Bathurst St., Room 2MC405, Toronto, Ontario, Canada M5T 2S8. Address e-mail to beheiry{at}uhnres.utoronto.ca.

BACKGROUND: High-dose opioid therapy can precipitate seizures; however, the mechanism of such a dangerous adverse effect remains poorly understood. The aim of our study was to determine whether the neuroexcitatory activity of high-dose morphine is mediated by selective stimulation of opioid receptors.

METHODS: Mice hippocampi were resected intact and bathed in low magnesium artificial cerebrospinal fluid to induce spontaneous seizure-like events recorded from CA1 neurons.

RESULTS: Application of morphine had a biphasic effect on the recorded spontaneous seizure-like events. In a low concentration (10 µM), morphine depressed electrographic seizure activity. Higher morphine concentrations (30 and 100 µM) enhanced seizure activity in an apparent dose-dependent manner. Naloxone, a nonselective opiate antagonist blocked the proconvulsant action of morphine. Selective µ and opiate receptor agonists and antagonists enhanced and suppressed the spontaneous seizure activity, respectively. On the contrary, opioid receptor ligands did not have an effect.

CONCLUSIONS: The proseizure effect of morphine is mediated through selective stimulation of µ and opiate receptors but not the activation of the receptor system. The observed dose-dependent mechanism of morphine neuroexcitation underscores careful adjustment and individualized opioid dosing in the clinical setting.

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