Mechanisms of morphine enhancement of spontaneous seizure activity.
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 microM), morphine depressed electrographic seizure activity. Higher morphine concentrations (30 and 100 microM) enhanced seizure activity in an apparent dose-dependent manner. Naloxone, a nonselective opiate antagonist blocked the proconvulsant action of morphine. Selective mu and kappa opiate receptor agonists and antagonists enhanced and suppressed the spontaneous seizure activity, respectively. On the contrary, delta opioid receptor ligands did not have an effect.


CONCLUSIONS
The proseizure effect of morphine is mediated through selective stimulation of mu and kappa opiate receptors but not the activation of the delta receptor system. The observed dose-dependent mechanism of morphine neuroexcitation underscores careful adjustment and individualized opioid dosing in the clinical setting.
Toronto Western Research Institute, University of Toronto, University Health Network, Toronto, Ontario, Canada.
Ehsan
E
Saboory
Miron
M
Derchansky
Mohammed
M
Ismaili
Shokrollah S
SS
Jahromi
Richard
R
Brull
Peter L
PL
Carlen
Hossam
H
El Beheiry
D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000633:toxicity*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology*
D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009020:Morphine