ABSTRACT
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.
Subject(s)
Morphine/toxicity , Seizures/chemically induced , Seizures/physiopathology , Animals , Animals, Newborn , Dose-Response Relationship, Drug , Hippocampus/drug effects , Hippocampus/physiology , Mice , Mice, Inbred C57BL , Receptors, Opioid, kappa/agonists , Receptors, Opioid, kappa/physiology , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/physiologyABSTRACT
The existence of hippocampal high-frequency electrical activities (greater than 100 Hz) during the progression of seizure episodes in both human and animal experimental models of epilepsy has been well documented (Bragin A, Engel J, Wilson C L, Fried I and Buzsáki G 1999 Hippocampus 9 137-42; Khosravani H, Pinnegar C R, Mitchell J R, Bardakjian B L, Federico P and Carlen P L 2005 Epilepsia 46 1-10). However, this information has not been studied between successive seizure episodes or utilized in the application of seizure classification. In this study, we examine the dynamical changes of an in vitro low Mg2+ rat hippocampal slice model of epilepsy at different frequency bands using wavelet transforms and artificial neural networks. By dividing the time-frequency spectrum of each seizure-like event (SLE) into frequency bins, we can analyze their burst-to-burst variations within individual SLEs as well as between successive SLE episodes. Wavelet energy and wavelet entropy are estimated for intracellular and extracellular electrical recordings using sufficiently high sampling rates (10 kHz). We demonstrate that the activities of high-frequency oscillations in the 100-400 Hz range increase as the slice approaches SLE onsets and in later episodes of SLEs. Utilizing the time-dependent relationship between different frequency bands, we can achieve frequency-dependent state classification. We demonstrate that activities in the frequency range 100-400 Hz are critical for the accurate classification of the different states of electrographic seizure-like episodes (containing interictal, preictal and ictal states) in brain slices undergoing recurrent spontaneous SLEs. While preictal activities can be classified with an average accuracy of 77.4 +/- 6.7% utilizing the frequency spectrum in the range 0-400 Hz, we can also achieve a similar level of accuracy by using a nonlinear relationship between 100-400 Hz and <4 Hz frequency bands only.
Subject(s)
Biological Clocks , Diagnosis, Computer-Assisted/methods , Electroencephalography/methods , Epilepsy/diagnosis , Epilepsy/physiopathology , Hippocampus/physiopathology , Pattern Recognition, Automated/methods , Action Potentials , Animals , Artificial Intelligence , Brain/physiopathology , Epilepsy/classification , In Vitro Techniques , Male , Neural Networks, Computer , Rats , Rats, WistarABSTRACT
Gap junctions (gjs) are increasingly recognized as playing a significant role in seizures. We demonstrate that different types of gap junctional blocking agents reduce the duration of evoked seizure-like primary afterdischarges (PADs) in the rat in vitro CA1 hippocampal pyramidal region, following repetitive tetanization of the Schaffer collaterals. Intracellular acidosis, which is known to block gap junctional communication, decreased the PADs, whereas alkalinization increased the PADs. Cellular excitability was not significantly depressed as determined by input/output relations recorded before and during perfusion of the gj blockers blockers carbenoxolone and sodium propionate. There was a small decrease following 1-octanol perfusion and a large decrease following NH(4)Cl application. Carbenoxolone diminished PAD duration, but increased neuronal excitability in whole-cell recordings. After robust PADs were established, the expression of several gj proteins including connexins (Cxs) 26, 32, 36, and 43, as measured by Western blotting, was unchanged, although the level of nonphosphorylated Cx43 was decreased. Our data support the concept that blocking gap junctional communication is an anticonvulsant mechanism.
