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 κ opiate receptor agonists and antagonists enhanced and suppressed the spontaneous seizure activity, respectively. On the contrary, δ opioid receptor ligands did not have an effect.
CONCLUSIONS: The proseizure effect of morphine is mediated through selective stimulation of μ and κ opiate receptors but not the activation of the δ receptor system. The observed dose-dependent mechanism of morphine neuroexcitation underscores careful adjustment and individualized opioid dosing in the clinical setting.