beta-endorphin and Epilepsy

The localization of opioid peptides in the rat hippocampal formation and the epileptogenic action of beta-endorphin and certain enkephalin analogues have led to speculations that opioids may play a role in limbic seizures. These immunochemical and electroencephalographic data are compatible with single-unit electrophysiological studies showing predominant excitations of hippocampal pyramidal neurons in CA1 and CA3 fields produced by iontophoresis of endorphins or enkephalins. These excitations are naloxone sensitive and appear to arise from a disinhibitory mechanism due to inhibition of inhibitory interneurons. Thus, intracellular recordings in in vitro preparations of hippocampus usually show opioid-induced reduction of inhibitory postsynaptic potentials. However, more recent studies suggest that a major opioid-containing pathway in the hippocampus, the mossy fiber projection from the dentate gyrus to CA3 pyramidal neurons, contains more pro-dynorphin-derived peptides than pro-enkephalin. Intracerebroventricular dynorphin does not induce epileptiform activity in the rat, and single-unit and field-potential studies show mixed effects on CA3 neuronal excitability, with more inhibitory responses than are seen with the enkephalins. Selective inactivation of mu opioid receptors reveals that dynorphin, which was previously shown to express specificity for kappa receptors, can act on delta receptors in CA1. Furthermore, a specific kappa agonist, U50,488H, has inhibitory actions when applied directly to CA3 neurons. These data suggest the presence of multiple opioid receptor types in the hippocampus. These multiple receptors may point to heterogeneous functions of the different families of opioid peptides in various regions of the hippocampus, and could explain the divergent effects reported for the various opioids and naloxone to promote or prevent paroxysmal activity.

Topics: Animals; beta-Endorphin; Biomechanical Phenomena; Endorphins; Enkephalins; Epilepsy; Hippocampus; Limbic System; Rats; Tissue Distribution

Topics: Analgesia; Animals; Asthma; beta-Endorphin; Diabetes Mellitus; Endorphins; Enkephalins; Epilepsy; Humans; Mental Disorders; Pituitary Hormones, Anterior; Receptors, Opioid; Tissue Distribution

We measured beta-endorphin concentrations in the anterior and neurointermediate lobes of the pituitary gland and in microdissected brain regions of moderate-seizure genetically epilepsy-prone rats (GEPR-3), severe-seizure GEPR-9s and Sprague-Dawley non-epileptic control rats. Plasma concentrations of beta-endorphin and beta-melanocyte-stimulating hormone (alpha-MSH) were also measured as indicators of pituitary POMC-peptide secretion. Concentrations of beta-endorphin in the anterior lobe of GEPR-3s were 53% higher compared to controls and 57% higher compared to GEPR-9s. There were no differences in neurointermediate lobe beta-endorphin concentrations between control and either GEPR strain. Plasma beta-endorphin concentrations were significantly lower in GEPR-9s than controls. Plasma levels of alpha-MSH did not differ between control and GEPRs. In the hypothalamus of GEPR-9s beta-endorphin concentrations in the arcuate nucleus were significantly greater than in GEPR-3s. Concentrations of beta-endorphin in the central amygdala of GEPR-9s were two- to threefold greater than in control or GEPR-3s. Beta-Endorphin concentrations in the central gray of GEPR-3s were 58% lower than control or GEPR-9s. These data suggest that anterior lobe beta-endorphin secretion is reduced in GEPR-9s. Furthermore, brain endorphinergic pathways appear to be differentially altered in GEPR-3s and GEPR-9s. Alterations in pituitary beta-endorphin secretion and brain endorphinergic systems may contribute to seizure susceptibility in GEPRs and to differences in seizure severity between GEPR-3s and GEPR-9s.

Topics: alpha-MSH; Animals; beta-Endorphin; Brain Chemistry; Epilepsy; Pituitary Gland; Pituitary Gland, Anterior; Radioimmunoassay; Rats; Rats, Sprague-Dawley

Recent experimental data indicate that endogenous brain ligands for the opioid receptors such as enkephalins, beta-endorphin (beta-End) and dynorphin (Dyn) may be involved in both generalized and partial seizures. The "tottering" (tg/tg) mouse provides an electrophysiological representation of generalized spontaneous human epilepsy. These mice exhibit behavioral absence seizures with accompanying spike-wave discharges. Methionine-enkephalin (M-Enk), beta-End and Dyn levels in various regions of brain were measured by radioimmunoassay (RIA) in 15-18-week-old tg/tg and control (+/+) mice to elucidate the relation between seizures and the opioid system. beta-End and Dyn levels were similar in tg/tg and +/+ mice. However, M-Enk levels were significantly increased in the striatum, cortex, pons and medulla of the tg/tg mice. Our data suggest that in the tottering mouse model of generalized epilepsy there is an alteration of enkephalinergic pathways and not of the endorphinergic or dynorphinergic pathways.

Topics: Animals; beta-Endorphin; Brain; Dynorphins; Enkephalin, Methionine; Epilepsy; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Osmolar Concentration; Radioimmunoassay; Tissue Distribution

By means of RIA, the contents of Leu-enkephalin, Met-enkephalin, and Beta-endorphin in CSF of 32 epileptic patients and 24 controls were determined. It was found that the mean Leu-enkephalin content in CSF of the epileptic patient group was significantly higher than that of the control group (P less than 0.01), whereas the mean contents of Met-enkephalin and Beta-endorphin in CSF showed no significant change as compared with those of the control group. The increase of Leu-enkephalin was not related to such factors as type of seizure, age of onset, length of time after the last seizure, taking of antiepileptic drugs, and abnormality in cranial CT manifestation. This suggested that endogenous opioid peptides might take part in the neurochemical mechanism of human epilepsy, and leu-enkephalin could play an important role in the development of epileptic episodes.

Topics: Adolescent; Adult; beta-Endorphin; Child; Enkephalin, Leucine; Enkephalin, Methionine; Epilepsies, Partial; Epilepsy; Female; Humans; Male; Middle Aged

Neuropeptides have been proposed to play a role in regulation of the seizure threshold and interictal behavior in experimental models of epilepsy, but there are few studies concerning neuropeptides in human epilepsy. We compared the levels of two peptides, somatostatin (SLI) and beta-endorphin (BEP) in lumbar cerebrospinal fluid (CSF) of unmedicated (N = 18) and medicated (n = 24) epileptic patients with the levels of these peptides in control (n = 20). Peptide levels in the CSF of patients with panic disorder (8) were also evaluated. Patients with chronic medicated epilepsy had a SLl level 80% (p = 0.003, Mann-Whitney U-test) that of the controls, 76% (p = 0.011) that of unmedicated patients, and 84% (p = 0.028) that of the panic group. BEP in the CSF did not differ in unmedicated, medicated and control patients. On the other hand, patients with panic disorder had higher levels of BEP in CSF than did the controls (117%, p = 0.041). In panic patients SLl was at control level. The present study indicates that the peptidergic systems are affected differentially in epilepsy and in panic disorder. Furthermore, there seems to be selectivity in the affect on peptidergic systems during the period when the epilepsy becomes chronic.

Topics: Adolescent; Adult; Anticonvulsants; beta-Endorphin; Epilepsy; Female; Humans; Male; Middle Aged; Phobic Disorders; Radioimmunoassay; Somatostatin

The anticonvulsant action of the new anticonvulsant drug gamma-vinyl-GABA (GVG) is obviously mediated by elevation of the concentration of GABA in the brain. The effect of GVG administration on other transmitter systems is not fully known in humans. We studied the possible interactions of GVG administration with peptidergic systems. Included in this study were 67 patients with complex partial epilepsy (CPS). The first CSF sample was taken before GVG administration. The second CSF sample was taken after 3 months of GVG treatment (3 g/day). Thereafter half of the responders (50% decrease in seizure frequency or clear improvement in global performance) received 3 g/day and the other half received 1.5 g/day for the next three months, after which the third CSF sample was taken. Somatostatin (SLI), beta-endorphin (beta-EP), and prolactin (PROL) levels in CSF were measured by radioimmunoassay. Total GABA (tGABA) and GVG levels in CSF were measured by high performance liquid chromatography. After 3 months of GVG treatment there was a slight increase in the beta-EP (p = 0.027, Student's paired t-test), which was not found after 6 months of GVG administration. Both SLI and PROL were stable during the study. Peptide levels were not connected to the clinical response to GVG, GVG dosage, or to tGABA levels in the CSF. In conclusion, the elevation of GABA levels in the brain during GVG treatment apparently does not induce long-term interactions with the peptidergic systems studied.

Topics: Adult; Aminocaproates; Anticonvulsants; beta-Endorphin; Endorphins; Epilepsy; Humans; Prolactin; Radioimmunoassay; Somatostatin; Vigabatrin

The possible role of different peptidergic systems in the postictal stage of human epilepsy was studied by measuring beta-endorphin, somatostatin, and prolactin levels by radioimmunoassay of cerebrospinal fluid (CSF) from nine epileptic patients. The first sample was taken within 2 hours after generalised tonic-clonic convulsion, and the second sample was obtained interictally after 1-4 days without any kind of clinically observable seizures. beta-endorphin was elevated postictally (p = 0.044) compared with interictal levels. SLI and PROL were similar in both samples. The present study suggests that in humans beta-endorphin is released into CSF during generalised seizures. This may indicate that neurons containing beta-endorphin are activated during a seizure.

Topics: Adult; beta-Endorphin; Epilepsy; Epilepsy, Temporal Lobe; Female; Humans; Male; Middle Aged; Prolactin; Somatostatin

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Brain; Corticotropin-Releasing Hormone; Electroencephalography; Endorphins; Epilepsy; Evoked Potentials; Frontal Lobe; Hippocampus; Hydrocortisone; Kindling, Neurologic; Male; Naloxone; Rabbits

Topics: Adolescent; Adult; Aggression; beta-Endorphin; Electric Stimulation; Endorphins; Epilepsy; Female; Humans; Male; Psychotic Disorders

Repeated spaced injection of small amounts of beta-endorphin or Met-enkephalin into the hippocampus or posterior amygdala of the rat led to the development of kindled generalized convulsions. Similar injection of morphine into the hippocampus or anterior amygdala resulted in epileptiform spiking followed by tolerance. The epileptiform spiking and convulsive behavior varied in a dose-related manner. Naloxone blocked or greatly attenuated the electrographic seizure and convulsive behavior. Prior kindling with beta-endorphin or Met-enkephalin significantly facilitated electrical kindling of the amygdala. Handling or conspecific threat potentiated the epileptiform spiking and convulsive behavior in some cases. The results indicate that the epileptogenic response to intracerebrally applied opioid peptides is site-specific within the rat brain, and they support the idea that endogenous opioid mechanisms may play a role in convulsive seizures. They also suggest a possible opiate-based mechanism for the stress-induced exacerbation of seizures.

Topics: Amygdala; Animals; beta-Endorphin; Convulsants; Electric Stimulation; Endorphins; Enkephalin, Methionine; Epilepsy; Handling, Psychological; Hippocampus; Kindling, Neurologic; Male; Morphine; Rats

As more small peptidergic components of the central nervous system are isolated, their role in disease states is being investigated. Several of these neuropeptides, especially the opioidlike peptides, adrenocorticotropic hormone, and some hypothalamic releasing factors, have been found to alter neuronal excitability. This finding has led to the proposal that these peptides may play a role in the pathogenesis of the epilepsies. We tested this hypothesis in a genetic model of epilepsy. At nontoxic doses, several exogenously administered peptides had anticonvulsant properties, while others were proconvulsant. The most potent anticonvulsant was the opioidlike peptide beta-endorphin. Its effect was similar to that of the opioid alkaloids. Using the potent antagonist naloxone hydrochloride to block possible endogenous opioid-like peptides, we found no effects on seizures in naive animals. Naloxone did alter postictal events, however, by partially blocking the postictal refractoriness to further seizures. We speculate that one possible role for the endogenous opioid peptides may be to limit the spread of seizures or to modulate postictal susceptibility to further seizures. Naloxone was effective in this model only after stressful situations occurred that modified the seizures and presumably induced a release of endogenous opioidlike peptides. Support for this hypothesis from other epilepsy models is discussed. Other peptidergic systems may also be active in various epileptic models, and the current understanding of their roles is reviewed.

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Brain; Endorphins; Epilepsy; Gerbillinae; Naloxone; Peptide Fragments; Receptors, Opioid; Synaptic Transmission; Thyrotropin-Releasing Hormone; Vasopressins

We studied the hormonal responses to a generalized tonic-clonic convulsion in 20 patients with idiopathic or posttraumatic epilepsy (6 patients) or alcohol-withdrawal seizures (14 patients). We found an increase shortly after the seizure in plasma levels of ACTH, beta endorphin, beta lipotropin, prolactin, and vasopressin, and a later increase in plasma cortisol. There was no significant change in levels of growth hormone, luteinizing hormone, follicular stimulating hormone, or plasma renin activity. An increase in plasma ACTH level was accompanied by a rise in beta lipotropin and beta endorphin, and followed by a rise in plasma cortisol. In 2 patients there was no postictal increase in plasma prolactin, despite changes in other hormones. There was no difference in the nature or time course of the hormonal changes in patients with alcohol-withdrawal seizures and those with seizures from other causes. The mechanisms subserving these changes are unknown. Nonspecific stress influences the release of certain hormones, but the absence of a significant growth hormone response suggests that this was probably not responsible for our findings. It is possible that the generalized neuronal discharge of a seizure stimulates the hypothalamus either directly, through specific neurotransmitter changes, or through the release of other substances. One possibility that we are investigating in experimental animals is that endogenous opioids are involved, especially in the release of prolactin.

Topics: Adrenocorticotropic Hormone; Adult; Aged; beta-Endorphin; beta-Lipotropin; Endorphins; Epilepsies, Myoclonic; Epilepsy; Epilepsy, Post-Traumatic; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Male; Middle Aged; Prolactin; Renin; Somatostatin

The naturally epileptic Mongolian gerbil was used to investigate the epileptogenic properties of beta-endorphin, dynorphin, met-enkephalin and morphine. The results indicate that opioid induced "seizures" are different from naturally spontaneous seizures in the gerbil in respect to EEG recording and motor behavior. Evidence for a protective role in preventing seizures is also presented.

Topics: Animals; beta-Endorphin; Cerebral Cortex; Dynorphins; Endorphins; Enkephalin, Methionine; Epilepsy; Gerbillinae; Morphine; Naltrexone; Narcotics; Seizures

The present authors gave mu, delta, kappa, epsilon and sigma opiate receptor agonists intracerebroventricularly to rats both singly and in combination while monitoring the electroencephalogram from cortical and depth electrodes. Dose-response curves were plotted with naloxone against the changes produced by each agonist, and the effect of a number of anticonvulsant drugs on agonist-induced seizures was ascertained. Each opiate agonist produced a different seizure pattern with a different naloxone dose-response curve and anticonvulsant profile. The order of convulsive potency was epsilon greater than delta greater than mu greater than sigma much greater than kappa. Petit mal-like seizure activity was unique to the delta agonist, leucine-enkephalin, while only the mu agonist, morphine produced generalized convulsive seizures. These experiments raise the possibility that opiate systems in the brain may be involved in the pathogenesis of a wide spectrum of seizure disorders.

Topics: Animals; Anticonvulsants; beta-Endorphin; Cyclazocine; Electroencephalography; Endorphins; Enkephalin, Leucine; Epilepsy; Ethylketocyclazocine; Injections, Intraventricular; Male; Naloxone; Narcotics; Phenazocine; Rats; Rats, Inbred Strains