naloxone and Epilepsy--Temporal-Lobe

1. Amygdaloid kindled seizures in rats produce postictal motor deficits, disruption of affective responding to sensory input, postictal explosiveness, and seizure suppression that may be similar to events following complex partial seizures in humans. 2. Preliminary 2DG studies in kindled rats indicate that postictal motor deficits may be mediated by the substantia nigra. Disruption of affective responding and postictal seizure suppression may be mediated by the hippocampus. 3. Data from the literature indicates that postictal motor deficits may be mediated by mu and kappa opioid receptors. The disruption of affective responding may be mediated primarily be delta and maybe also by kappa receptors. Postictal explosiveness may involve either a non-mu receptor or it may be a non-opioid effect. Kindling-induced postictal seizure suppression may be mediated by kappa receptors and perhaps also by mu receptors. 4. Mechanisms underlying postictal effects of complex partial seizures in humans are suggested by the data in this manuscript. New approaches to the treatment of these postictal events are also proposed.

Topics: Animals; Deoxyglucose; Disease Models, Animal; Endorphins; Epilepsy, Temporal Lobe; Limbic System; Motor Activity; Naloxone; Rats; Receptors, Opioid

The endogenous kappa receptor selective opioid peptide dynorphin has been shown to inhibit glutamate receptor-mediated neurotransmission and voltage-dependent Ca2+ channels. It is thought that dynorphin can be released from hippocampal dentate granule cells in an activity-dependent manner. Since actions of dynorphin may be important in limiting excitability in human epilepsy, we have investigated its effects on voltage-dependent Ca2+ channels in dentate granule cells isolated from hippocampi removed during epilepsy surgery. One group of patients showed classical Ammon's horn sclerosis characterized by segmental neuronal cell loss and astrogliosis. Prominent dynorphin-immunoreactive axon terminals were present in the inner molecular layer of the dentate gyrus, indicating pronounced recurrent mossy fiber sprouting. A second group displayed lesions in the temporal lobe that did not involve the hippocampus proper. All except one of these specimens showed a normal pattern of dynorphin immunoreactivity confined to dentate granule cell somata and their mossy fiber terminals in the hilus and CA3 region. In patients without mossy fiber sprouting the application of the kappa receptor selective opioid agonist dynorphin A ([D-Arg6]1-13, 1 microM) caused a reversible and dose-dependent depression of voltage-dependent Ca2+ channels in most granule cells. These effects could be antagonized by the non-selective opioid antagonist naloxone (1 microM). In contrast, significantly less dentate granule cells displayed inhibition of Ca2+ channels by dynorphin A in patients with mossy fiber sprouting (Chi-square test, P < 0.0005). The lack of dynorphin A effects in patients showing mossy fiber sprouting compares well to the loss of kappa receptors on granule cells in Ammon's horn sclerosis but not lesion-associated epilepsy. Our data suggest that a protective mechanism exerted by dynorphin release and activation of kappa receptors may be lost in hippocampi with recurrent mossy fiber sprouting.

Topics: Adolescent; Adult; Age of Onset; Axons; Calcium Channels, N-Type; Child; Dentate Gyrus; Dynorphins; Electric Stimulation; Epilepsy, Temporal Lobe; Female; Hippocampus; Humans; In Vitro Techniques; Male; Middle Aged; Naloxone; Nerve Endings; Nerve Fibers; Neurons; Patch-Clamp Techniques; Pyramidal Cells; Sclerosis

The distribution of dynorphin (DYN), one of its binding sites (kappa 1 receptor) and their relationship to neuronal loss and granule cell hyperexcitability was examined in hippocampi from patients with temporal lobe epilepsy (TLE). In hippocampi that were not the seizure focus (mass associated temporal lobe epilepsy, MaTLE; and paradoxical temporal lobe epilepsy, PTLE) DYN-like immunoreactivity was localized in the dentate granule cells and their mossy fiber terminals within the hilus and area CA3. In hippocampi that were the seizure focus (MTLE), 89% showed an additional band of immunoreactivity confined to the inner molecular layer (IML) of the dentate gyrus, representing recurrent mossy fiber collaterals. In 11% of MTLE patients no staining was found in the IML (MTLE/DYN-). The MTLE/DYN- hippocampi were also characterized by a significantly lower degree of cell loss than in MTLE hippocampi in the dentate granule cell layer, the hilus and CA3. Both MTLE and MTLE/DYN- hippocampi showed evoked epileptiform bursting in granule cells while MTLE showed greater polysynaptic EPSPs and spontaneous excitatory activity. Thus granule cell recurrent collateral sprouting may account for only some aspects of hyperexcitability. In 30% of the MTLE group, hilar neurons of a variety of morphological types expressed DYN immunoreactivity in their somata and dendrites. The density of [3H]U69,593 binding sites in MaTLE and PTLE patients was highest in areas CA1 and the subiculum-regions having little or no DYN-staining. In the dentate molecular layer, hilus and CA3--regions with the most DYN immunoreactivity--there was a low density of ligand binding. The significance of this transmitter/receptor mismatch is yet unknown.

Topics: Adolescent; Adult; Benzeneacetamides; Binding Sites; Cell Count; Dynorphins; Epilepsy, Temporal Lobe; Female; Hippocampus; Humans; Male; Middle Aged; Naloxone; Neurons; Pyrrolidines; Receptors, Opioid, kappa; Tritium

A Bull Terrier that was continuously chasing its tail was examined clinically, electroencephalographically, and by computed tomography of the head. The dog was also given test treatments with an anticonvulsant (diazepam) and a pure opioid antagonist (naloxone). The dog appeared to be hysterical and dissociated from its surroundings. Electroencephalography revealed a seizure pattern that was most marked over the temporal lobe, and computed tomography revealed mild hydrocephalus. Diazepam effectively controlled tail chasing, whereas naloxone did not. The dog was discharged on anticonvulsant therapy but subsequently had to be euthanatized when aggression developed. Results of examination and treatment have led the investigators to propose a hereditary mechanism for tail chasing, perhaps related to zinc malabsorption.

Topics: Aggression; Animals; Behavior, Animal; Diazepam; Dog Diseases; Dogs; Electroencephalography; Epilepsy, Temporal Lobe; Hydrocephalus; Male; Naloxone; Phenobarbital; Stereotyped Behavior