Lack of Effect of Naloxone on Prolactin and Seizures in Electroconvulsive Therapy

Both opiate agonist and antagonist injection have been reported to modulate prolactin secretion, alter brain excitability and produce seizures, and modify the postictal state. We studied the effects of administration of high-dose naloxone, an opiate antagonist, on postictal prolactin levels, seizure duration, and postictal behavior, using patients undergoing electroconvulsive therapy (ECT) as a seizure model. Seven patients had 8 mg naloxone injected prior to one ECT treatment and saline injected prior to another treatment, with the order of injection randomized. Before ECT and 15 min after ECT, prolactin levels were drawn, and no blunting of the expected postictal prolactin elevation by naloxone injection was observed. We found no evidence that endogenous opiates trigger prolactin secretion during seizures. Seizure duration was also similar in saline and naloxone groups, and naloxone did not reverse postictal depression, as has been reported in an animal model.     

Naloxone fails to prolong seizure length in ECT

Electroconvulsive shock (ECS) in animals has been shown to enhance endogenous opiate systems. The anticonvulsant effects of ECS are also partially blocked by the opiate receptor antagonist naloxone, leading some investigators to postulate that the anticonvulsant effects of ECS are mediated by activation of endogenous opiates. If such a phenomenon occurs in humans, then naloxone might prolong seizure length in electroconvulsive therapy (ECT). In the present study, nine patients were given 2.0 mg intravenous (i.v.) naloxone 2 minutes prior to one-half of their ECT treatments. Motor seizure length was measured via the cuff technique. EEG tracings were read by an investigator blind to naloxone status. There was no difference between the two groups in either EEG or nonblindly evaluated motor seizure length. It is concluded that a dose of 2 mg naloxone does not effectively increase seizure length in ECT.     

Anticonvulsant Activity of Felbamate in Amygdala Kindling Model of Temporal Lobe Epilepsy in Rats

Summary: Purpose : Previous studies have demonstrated that felbamate (FBM, 2-phenyl-1,3-propanediol dicarbamate) at nontoxic doses exerts potent anticonvulsant activity in a variety of animal epilepsy or seizure models. We further characterized the anticonvulsant activity of FBM by using the kindling model of temporal lobe epilepsy (TLE).
Methods : The experiments were performed in fully kindled rats. The anticonvulsant effect of FBM was assessed by determining seizure severity, after discharge (AD) duration and seizure duration either at the focal seizure threshold, or after supra threshold stimulation. In addition, the neurological performance of kindled rats after FBM administration was evaluated in the open field and by the rotorod test.
Results : FBM at doses of 12.5–50 mg/kg, given intraperitoneally (i.p.) 60 min before testing, dose-dependently increased the AD threshold (ADT). The maximal effect was achieved after the highest dose tested and reached almost 600% of the control ADT. This dose of FBM significantly diminished other seizure parameters, e.g., seizure severity, seizure duration, and AD duration. When the rats were stimulated with suprathreshold current (500 μA) seizure severity was moderately but significantly reduced. No behavioral abnormalities were noted in kindled rats after administration of either of the doses.
Conclusions : FBM potently increases the threshold for focal seizures and reduces seizure severity, seizure duration, and AD duration at doses that produce no adverse behavioral effects in amygdala-kindled rats. These data are thus compatible with clinical experience with FBM in TLE and substantiate that kindling is a good predictor of anticonvulsant activity against TLE.     

Opioid-induced epileptogenic phenomena: anatomical, behavioral, and electroencephalographic features

Recent animal studies have indicated a possible role of opioids in epilepsy. Intraventricular opioid administration induces a prolonged nonconvulsive stuporous state characterized by epileptiform electroencephalographic patterns, and reversed by naloxone. In high doses, naloxone itself causes generalized clonic convulsions. We compared opioid-induced and naloxone-induced epileptogenic phenomena using quantitative 2-deoxyglucose autoradiography in order to define the anatomical structures involved in these two different seizure types. When opioid-induced seizures occurred, limbic structures were preferentially activated, but when naloxone-induced clonic convulsions occurred, pyramidal and extrapyramidal motor areas and some limbic structures were activated. Based on the present experiments and currently available evidence, we speculate that opioid-mediated epileptogenic phenomena are similar to those occurring during the postictal state of a fully kindled seizure, whereas naloxone-induced epileptogenic phenomena are similar to the ictal state. Therefore, simple pharmacological manipulation of endogenous opioid systems may allow selective study of ictal and postictal phenomena.     

Mu-opiate receptors measured by positron emission tomography are increased in temporal lobe epilepsy

Neurochemical studies in animal models of epilepsy have demonstrated the importance of multiple neurotransmitters and their receptors in mediating seizures. The role of opiate receptors and endogenous opioid peptides in seizure mechanisms is well developed and is the basis for measuring opiate receptors in patients with epilepsy. Patients with complex partial seizures due to unilateral temporal seizure foci were studied by positron emission tomography using 11C-carfentanil to measure mu-opiate receptors and 18F-fluoro-deoxy-D-glucose to measure glucose utilization. Opiate receptor binding is greater in the temporal neocortex on the side of the electrical focus than on the opposite side. Modeling studies indicate that the increase in binding is due to an increase in affinity or the number of unoccupied receptors. No significant asymmetry of 11C-carfentanil binding was detected in the amygdala or hippocampus. Glucose utilization correlated inversely with 11C-carfentanil binding in the temporal neocortex. Increased opiate receptors in the temporal neocortex may represent a tonic anticonvulsant system that limits the spread of electrical activity from other temporal lobe structures.     

Modulation of Endogenous Opioid Systems by Electroconvulsive Shock

Since the discovery of opioid peptides, the brain opioid system has been implicated in the pathophysiology of a spectrum of mental disorders, including depression and epilepsy. For example, a growing body of evidence demonstrates that these neuropeptides are activated by seizures. Specifically, using electroconvulsive shock, it has been possible to describe an array of antinociceptive, autonomic, behavioral, biochemical, and electroencephalographic responses that appear to be mediated by endogenously activated opioids. A primary role for opioid peptides as neuromodulators of postictal seizure arrest and refractoriness is now recognized, and the existence in the central nervous system (CNS) of an endogenous anticonvulsant substance activated by electroconvulsive shock (ECS) has been determined. This review focuses on the more recent developments regarding ECS-induced modulation of brain opioid systems. The ability of ECS to alter opioid receptors, to influence the release and biosynthesis of the various opioid peptides, and to activate endogenous anticonvulsant mechanisms will be addressed.     

Effect of a novel anticonvulsant, zonisamide (AD-810, CI-912), in an experimental model of photosensitive epilepsy

The effects of a novel anticonvulsant, zonisamide (3-sulfamoylmethyl-1,2-benzisoxazole), on photically induced seizures were studied in the lateral geniculate-kindled cat. Zonisamide was found to reduce the behavioral severity of seizure responses to photic stimulation in a dose-related manner. This anticonvulsant effect was only observed with doses that caused behavioral toxicity, but anticonvulsant action outlasted behavioral effects. The present results suggest that zonisamide may be effective in the treatment of human photosensitive epilepsy.     

In vivo studies on the mechanism of action of the broad spectrum anticonvulsant loreclezole.

In animal models of epilepsy the anticonvulsant profile of loreclezole resembles that of barbiturates and benzodiazepines. We examined whether the increase in seizure threshold to pentylenetetrazole infusion produced by 10 mg/kg of loreclezole, pentobarbital or diazepam could be reversed by a spectrum of benzodiazepine partial inverse to full inverse agonists (FG-7142 beta-carboline carboxylate, CGS-8216, Ro-15-4513 and DMCM) or by a benzodiazepine neutral antagonist (Ro-15-1788). The doses of the benzodiazepine inverse agonists were chosen to produce a 20-40% decrease in seizure threshold. The seizure threshold increase produced by loreclezole and pentobarbital was reduced by all the benzodiazepine inverse agonists and potentiated by Ro-15-1788. Diazepam was antagonized by the benzodiazepine inverse agonists and by the neutral antagonist. The generality of this finding was examined in amygdala-kindled rats. The decrease in the duration of forepaw clonus and the reduction in behavioural stage34 produced by loreclezole, pentobarbital and diazepam was reversed by CGS-8216. Ro-15-1788, which itself showed anticonvulsant effects in this model, antagonized the effects of diazepam, but not loreclezole or pentobarbital. Thus loreclezole behaves more like a barbiturate than a benzodiazepine in these two in vivo models. This suggests a possible mechanism of action of loreclezole at a neuromodulatory site within the GABAA receptor complex, which is unlikely to be a benzodiazepine receptor.     

Adenosine and epilepsy: from therapeutic rationale to new therapeutic strategies.

Adenosine, as the brain's endogenous anticonvulsant, is considered to be responsible for seizure arrest and postictal refractoriness. On the other hand, deficiencies within the adenosine-based neuromodulatory system may contribute to epileptogenesis. Based on these natural mechanisms and on findings that adenosine and its analogs can suppress pharmacoresistant seizures, a new field of adenosine-based therapies has emerged, including the use of adenosine receptor agonists and adenosine transport inhibitors, or the inhibition of adenosine kinase, which is thought to be the key enzyme for the regulation of intra- and extracellular adenosine levels. However, most of these pharmacological approaches are limited by strong systemic side effects ranging from a decrease of heart rate, blood pressure, and body temperature to sedation. Recently, new strategies have been developed aimed at the local reconstitution of the inhibitory adenosinergic tone by intracerebral implantation of cells engineered to release adenosine. Adenosine-releasing cells or devices implanted into or near a seizure focus offer new hopes for a side effect-free therapy for pharmacoresistant epilepsy.     

Effects of chronic naloxone pretreatment on amygdaloid kindling in rats

Effects of chronic naloxone pretreatment (75 or 270, μg/h for 14 days) on the development of amygdaloid kindling in rats were evaluated. The acquisition of seizure activity was modified in the naloxone pretreated animals, depending on the nucleus stimulated: facilitation of stages IV and V occurred in 37%, variability of electrographic and behavioral responses to electrical stimulation during the kindling development in 33%, and facilitation of stages IV and V followed by long periods of seizure suppression in 29%. Enhancement of postictal seizure suppession during a recycling paradigm was observed in all the naloxone pretreated rats. It was concluded that the chronic administration of naloxone (known to induce opioid binding upregulation and supersensitivity), in association with the enduring changes in opioid mechanisms provoked by kindled seizures, were responsible for the facilitation and suppression of epileptic activity. These findings support bidirectional modulatory effects of opioid peptides on epileptic seizures as well as the view that epileptic seizures can induce enduring alterations in opioid mechanisms.     

Opiate-induced seizures: a study of mu and delta specific mechanisms

Two groups of experiments were conducted to determine if morphine- and enkephalin-induced seizures are specifically mediated by the mu and delta receptor, respectively. In the first experiments, designed to assess the ontogeny of mu- or delta-seizures, rats from 6 h to 85 days of age received implanted cortical and depth electrodes as well as an indwelling cannula in the lateral ventricle. Various amounts of the mu-receptor agonists, morphine and morphiceptin, and the delta agonists, D-Ala2-D-Leu5-enkephalin (DADL) and Tyr-D-Ser-Gly-Phe-Leu-Thr (DSLET), were then administered intracerebroventricularly (icv) with continuous EEG monitoring. The second experiments entailed use of the nonspecific opiate antagonist, naloxone, as well as the specific delta antagonist, ICI 154,129, against seizures induced by icv-administered morphine, morphiceptin, DADL, or DSLET. Both morphine and morphiceptin produced electrical seizure activity in rats as young as 5 days after birth. The drugs produced similar seizure activity in terms of electrical morphology, observed behavior, ontogeny, threshold dose, and reversibility with small doses of naloxone. In the pharmacologic experiments, icv naloxone blocked all opiate-induced seizures. ICI 154,129 blocked DSLET seizure, had little effect on enkephalin or DADL seizures, and no effect on morphine or morphiceptin seizures. These data indicate that DSLET seizures are delta-specific but that all other opiate-induced seizures studied may involve multiple opiate receptor-mediated mechanisms.     

Attenuation of reserpine-induced catalepsy by melatonin and the role of the opioid system

Several reports have indicated that melatonin influences motor activity in animals and humans. Melatonin has been reported to attenuate the rigidity and tremor of Parkinson's disease. Some of the behavioral effects (e.g., analgesic and anticonvulsant properties) of melatonin have been reported to be mediated through interactions with the endogenous opioid peptides. We investigated the effect of melatonin on reserpine-induced catalepsy in the rat and, additionally, examined whether this effect is modified by opioid peptides. Melatonin was found to attenuate markedly the duration of reserpine-induced catalepsy. These effects were potentiated by administration of the opiate agonist nalbuphine hydrochloride, while naloxone partially reversed the catalepsy reducing effect of melatonin. These findings suggest that the motor effects of melatonin may involve critical interactions with opioid peptides, and support the postulated reciprocal interactions between melatonin and opioid peptides that previously have been demonstrated for the analgesic and anticonvulsant properties of melatonin.     

Evaluation of different GABA receptor agonists in the kindled amygdala seizure model in rats

The effects of three specific GABA receptor agonists, muscimol, progabide, and gaboxadol, on kindled seizures were evaluated in amygdala-kindled rats. The only compound that exerted significant anticonvulsant effects at nonsedative doses was progabide. Thus, after i.p. administration of 100 mg/kg progabide, a significant increase in seizure latency and significant decreases in duration of motor seizures and amygdala afterdischarges were determined. A decrease in severity of motor seizures was found only after 200 mg/kg progabide which, however, gave rise to marked sedation and muscle relaxation. Muscimol and gaboxadol were almost inactive in attenuating kindled seizures even at doses that produced pronounced side effects. Assuming that the amygdala-kindled rat is a useful model of complex partial seizures with secondary generalization in the human, the data suggest that GABA receptor agonists are not effective against this type of epilepsy (muscimol, gaboxadol) or effective only at large doses (progabide).     

Double-blind cross-over placebo controlled study of flunarizine in patients with therapy resistant epilepsy

Twenty-five patients with long-standing therapy resistant epilepsy were studied in an eight-month double-blind cross-over add-on trial with a daily dose of 15 mg flunarizine. In five patients the seizure frequency decreased 50% or more. The mean seizure frequency reduction in the patients on flunarizine was 35%. Particularly the control of secondary generalized seizures improved. Flunarizine did not significantly alter the plasma levels of the regular anticonvulsant drugs. Minimal adverse side effects were reported equally in the flunarizine and the placebo group. In three patients depressive symptoms improved and two patients became free of postictal headaches. Flunarizine appears to be a safe adjuvant anticonvulsant.     

Influence of morphine and cyclazocine on the cortical epileptic foci in rabbits

The effects of morphine, cyclazocine and naloxone on penicillin- and strychnine-induced epileptic foci were studied in rabbits. The intracortical injection of penicillin (75, 150 and 300 units) elicited isolated spikes followed by repeated ictal events. The application of strychnine (0.062 and 0.125%) over the cortical surface of one side induced appearance of ipsilateral spiking spreading to the contralateral cortex.

Administration of morphine (0.25–0.75 mg/kg i.v.) or cyclazocine (0.05–3.0 mg/kg i.v.) inhibited the occurrence or the duration of the EEG and motor manifestations induced by penicillin (75 and 150 units) and strychnine (0.062 and 0.125%), while it did not influence the effect of 300 units of penicillin. High doses of morphine (up to 10 mg/kg i.v.) failed to affect the epileptic responses to penicillin and strychnine and at the same time significantly reduced the pO₂ in arterial blood.

Naloxone per se potentiated the effects of the lower doses of penicillin and strychnine. Only at very high doses (20 mg/kg i.v.) displayed a weak antagonism towards the anticonvulsant effect of the two opiates. A full antagonism is only observed towards the effect of cyclazocine (2 mg/kg i.v.) administered after penicillin.

Present data provide additional evidence of the heterogeneity of regulations by opioids of convulsive phenomena. One can hypothesize that the anticonvulsant effect of the two opiate agonists is mediated by naloxone-insensitive opiate receptors, while the proconvulsant-convulsant effect of naloxone might be related to an inhibition of GABA and glycine-mediated transmission.     

Anticonvulsant effects of nimodipine and two novel dihydropyridines (PCA 50922 and PCA 50941) against seizures elicited by pentylenetetrazole and electroconvulsive shock in mice

In animal models of epilepsy, calcium entry blockers have shown anticonvulsant properties. We studied the antiepileptic effects of nimodipine and two novel dihydropyridines, a calcium antagonist (PCA 50922) and a calcium agonist (PCA 50941), on pentylenetetrazole seizure and maximal electroshock seizure (MES) in mice. Anticonvulsant profile of nimodipine and PCA 50922 was similar to that of clonazepam, but markedly different from that of phenytoin. None of the doses of the PCA 50941 showed anticonvulsant effect.     

The involvement of endogenous opioids and nitricoxidergic pathway in the anticonvulsant effects of foot-shock stress in mice

The involvement of endogenous opioids and nitric oxide (NO) in the anticonvulsant effects of stress against pentylenetetrazole (PTZ)- or electroconvulsive shock-induced seizures was assessed in mice. The prolonged and intermittent foot-shock stress, which induced opioid-mediated analgesia, had significant protective effects against both seizure types which was reversible by naloxone (0.3, 1 or 2 mg/kg), while brief and continuous foot-shock did not alter the seizure susceptibility. Pre-treatment with non-specific nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 1, 2, 5, 10 or 30 mg/kg), but not with specific inducible NOS (iNOS) inhibitor, aminoguanidine (50 or 100 mg/kg), blocked the stress-induced anticonvulsant effects. The lower doses of naloxone (0.3 mg/kg) and L-NAME (2 mg/kg) showed additive effects in blocking the stress-induced anticonvulsant properties. L-arginine at a per se non-effective dose of 20 mg/kg potentiated the stress-induced anticonvulsant properties, an effect which was inhibited by L-NAME but not by aminoguanidine. Furthermore, a low dose of morphine (0.5 mg/kg) showed potentiation with stress in increasing PTZ seizure threshold. This potentiation was reversed by either naloxone or L-NAME at low doses but not by aminoguanidine. Taken together, these results show that NO synthesis, through constitutive but not iNOS, is involved in opioid-dependent stress-induced anticonvulsant effects against electrical and PTZ-induced convulsions.     

Opiate modulation of separation-induced distress in non-human primates

Infant rhesus monkeys respond to separation from their mothers with a dramatic increase in vocalizations and activation of autonomic and pituitary-adrenal systems. Using the mother-infant separation paradigm in rhesus monkeys, we focused on the role of opiate systems in modulating the behavioral and neuroendocrine consequences of a brief, naturally occurring stressor. In the first experiment, morphine 0.1 mg/kg significantly decreased separation-induced vocalizations without affecting activity levels. In the second experiment, naloxone 1.0 mg/kg increased distress vocalizations but lower doses had no effect. In the third experiment we blocked the effect of morphine 0.1 mg/kg with naloxone 0.1 mg/kg, a dose of naloxone that had no intrinsic effects of its own. This suggests that the reduction of separation-induced vocalizations by morphine is mediated by opiate receptors. The last experiment demonstrated that separation-induced increases in pituitary-adrenal hormones can also be modulated by opiate agonists and antagonists. These findings are consistent with work in non-primate species and support the hypothesis that opiate receptors are specifically involved in mediating separation-induced vocalizations and pituitary-adrenal activation in primates.     

Naloxone Ameliorates the Learning Deficit Induced by Pentylenetetrazol Kindling in Rats

Endogenous opioid peptides modulate and regulate processes of central excitability. Furthermore, opioids are thought to interfere with processes of learning and memory storage. In order to study the effects of endogenous opioids on both processes we injected in the course of development of pentylenetetrazol kindling the opiate receptor antagonist naloxone, and tested the animals afterwards in a shuttle-box task. It was found that naloxone pretreatment had dissociative effects. There was no effect on seizure outcome, whereas the learning deficit was ameliorated in the kindled group. The data suggest that endogenous opioid peptides contribute to the learning deficit found in pentylenetetrazol-kindled rats.     

Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1‐receptor antagonist in the rat

Purpose: Many patients with epilepsy are refractory to anticonvulsant drugs or do not tolerate side effects associated with the high doses required to fully prevent seizures. Antagonists of neurokinin‐1 (NK1) receptors have the potential to reduce seizure severity, although this potential has not been fully explored in animals or humans. The present study was designed to evaluate the efficacy of the NK1‐receptor antagonist, vofopitant, alone and in combination with different anticonvulsant drugs. Methods: Studies were conducted in rats using a model of generalized seizure induced by electroshock. Drug concentrations in blood and brain were determined in parallel to distinguish pharmacodynamic from pharmacokinetic interactions. Results: The NK1‐receptor antagonist, GR205171 (vofopitant) had no anticonvulsant efficacy by itself, but could potentiate the anticonvulsant efficacy of lamotrigine and other sodium channel blockers. However, GR205171 had no effect on the anticonvulsant potency of either valproate or gabapentin. GR205171 did not produce central nervous system (CNS) side effects at the doses tested, and it did not potentiate side effects induced by high doses of lamotrigine. The NK1‐receptor inactive enantiomer of GR205171 , GR226206 did not potentiate the efficacy of lamotrigine, suggesting that effects observed with GR205171 were mediated by NK1 receptors. Analysis of the dose–effect relationship for GR205171 indicated that a high (>99%) occupancy of NK1 receptors is required for effect, consistent with previous behavioral and human clinical studies with this pharmacologic class. Discussion: These results suggest that there may be benefit in adding treatment with a suitable NK1‐receptor antagonist to treatment with a sodium channel blocker in patients with refractory epilepsy.