naloxone and Seizures

Topics: Absorption; Administration, Intranasal; Analgesics, Opioid; Anesthetics, Local; Benzodiazepines; Biological Availability; Conscious Sedation; Emergency Nursing; Epistaxis; Humans; Hypnotics and Sedatives; Intubation, Gastrointestinal; Lidocaine; Naloxone; Narcotic Antagonists; Nasal Decongestants; Nasal Mucosa; Opioid-Related Disorders; Oxymetazoline; Seizures

There are four lines of evidence for or against a role of neuropeptides in epilepsy: Administration of a variety of opiate agonists into the ventricles or brain of animals produces a constellation of electrical and behavioral changes, seemingly receptor-specific, both sensitive to the specific opiate antagonist naloxone as well as certain anticonvulsant drugs. The primary reservation concerning these data in terms of their relevance to epilepsy regards the fact that the peptides are exogenously administered in relatively high doses. Hence, these data may reflect neurotoxic effects of peptides rather than physiologic function. A variety of opiate agonists are anticonvulsant and naloxone shortens the postictal state in some experimental seizure models. One could attempt to reconcile these data with those in No. 1 by hypothesizing that the spikes and behavioral changes examined in the latter experimental parodynes represented a sort of isolated model of the postictal state. Naloxone has little effect in clinical epilepsy. These data are far from conclusive for two reasons. First, few patients have been studied. Second, because of the issue of opiate receptor heterogeneity and the high doses of naloxone needed experimentally to block non-mu opiate effects, the doses of naloxone used clinically to date are too low to rule out possible delta- or epsilon-mediated effects. The negative clinical data are illustrative of the dangers and difficulties of extrapolating data generated in animal models of seizures to the human condition. ACTH, a peptide that is derived from the same precursor molecule as beta-endorphin, is clearly an effective anticonvulsant in certain childhood seizure states. However, whether this is due to a direct or indirect (that is, cortisol) effect on brain is far from clear. Paradoxically, in contradistinction to other data concerning pro- and anticonvulsant properties of various opioid peptides, there is no animal model of infantile spasms to help resolve this important question.

Topics: Adrenocorticotropic Hormone; Animals; Anticonvulsants; Brain; Endorphins; Humans; Naloxone; Receptors, Opioid; Seizures

Topics: Animals; Brain; Drug Interactions; Drug Tolerance; Electric Stimulation; Electroencephalography; Endorphins; Morphine; Naloxone; Rats; Receptors, Opioid; Seizures

Generalized tonic-clonic seizures (GTCSs) are the main risk factor for sudden unexpected death in epilepsy (SUDEP). Experimental and clinical data strongly suggest that the majority of SUDEP results from a postictal respiratory dysfunction progressing to terminal apnea. Postictal apnea could partly derive from a seizure-induced massive release of endogenous opioids. The main objective of this study is to evaluate the efficacy of an opioid antagonist, naloxone, administered in the immediate aftermath of a GTCS, in reducing the severity of the postictal central respiratory dysfunction.. The Efficacy of Naloxone in Reducing Postictal Central Respiratory Dysfunction in Patients with Epilepsy (ENALEPSY) study is a multicenter, double-blind, randomized, placebo-controlled trial conducted in patients with drug-resistant focal epilepsy who are undergoing long-term video-electroencephalogram (EEG) monitoring (LTM) in an epilepsy monitoring unit (EMU). We plan to randomize 166 patients (1:1) to receive intravenous naloxone (0.4 mg) or placebo in the immediate aftermath of a GTCS. Because inclusion in the study needs to take place prior to the occurrence of the GTCS, and because such occurrence is observed in about one-fourth of patients undergoing LTM, we plan to include a maximum of 700 patients upon admission in the EMU. The primary endpoint will be the proportion of patients whose oxygen saturation is <90 % between 1 and 3 min after the end of a GTCS. Secondary outcomes will include the following: the proportion of patients who show postictal apnea, the occurrence and duration of postictal generalized EEG suppression, the total duration of the postictal coma, postictal pain, and the number of patients who have a second GTCS within 120 min after the intravenous injection.. The demonstration of naloxone's efficacy on the severity of postictal hypoxemia will have two primary consequences. First, naloxone would be the first and only therapeutic approach that could be delivered immediately to reverse postictal apnea. Second, demonstration that an opioid antagonist can effectively reduce postictal apnea would pave the way for an assessment of a preventive therapy for SUDEP targeting the same pathophysiological pathway using oral administration of naltrexone.. ClinicalTrials.gov identifier: NCT02332447 . Registered on 5 January 2015.

Topics: Clinical Protocols; Double-Blind Method; Drug Administration Schedule; Electroencephalography; France; Humans; Hypoxia; Injections, Intravenous; Naloxone; Narcotic Antagonists; Research Design; Respiratory Center; Respiratory Insufficiency; Seizures; Severity of Illness Index; Time Factors; Treatment Outcome; Video Recording

Electroconvulsive therapy (ECT) is a highly effective treatment for major depression, but is also associated with characteristic cognitive side effects. Several reports document that endogenous opioids and their receptors are activated by electroconvulsive shock (ECS) and that naloxone in doses sufficient to block endogenous opioid receptors may reverse ECS-induced retrograde amnesia. This placebo-controlled, randomized, within-patient study was conducted to examine the potential of naloxone, given in doses sufficient to block opioid receptors (high dose), to ameliorate acute anterograde and retrograde memory impairments following ECT. Compared to placebo and low dose naloxone, high dose naloxone administered immediately before ECT resulted in significant reductions in anterograde amnesia, and better performance on an attention task. Both low and high dose naloxone improved verbal fluency. There were no beneficial effects of high dose naloxone on retrograde amnesia, and an indication that high dose naloxone may have worsened retrograde amnesia for shape stimuli. There were no effects of high dose naloxone on seizure duration, vital signs, and subjective side effects. The study is consistent with prior research in which change in behavioral and physiological measures was produced principally by naloxone doses sufficient to block endogenous opioid receptors and offers evidence of the potential for ameliorating some adverse cognitive effects associated with ECT.

Topics: Adult; Aged; Amnesia, Retrograde; Analysis of Variance; Cognition Disorders; Depressive Disorder; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Orientation; Placebos; Seizures; Treatment Outcome

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.

Topics: Adult; Aged; Depressive Disorder; Electroconvulsive Therapy; Female; Humans; Injections, Intravenous; Male; Middle Aged; Motor Activity; Naloxone; Narcotic Antagonists; Seizures; Time Factors

Naloxone is standard medication for the treatment of heroin intoxications. No large-scale studies have yet been carried out to determine its toxicity in heroin intoxications.. We have undertaken an investigation as to the frequency, type and degree of severity of complications attributable to naloxone administration. Subjects treated between 1991 and 1993 with naloxone for intravenous drug intoxications were prospectively evaluated.. Development of ventricular tachycardia or fibrillation; atrial fibrillation; asystole; pulmonary edema; convulsions; vomiting; and violent behavior within ten minutes after parenteral administration of naloxone.. Six of 453 intoxicated subjects (1.3%; 95% confidence interval 0.4%-3%) suffered severe adverse effects within ten minutes after naloxone administration (one asystole; three generalized convulsions; one pulmonary edema; and one violent behavior). After the ten minute period, no further complications were observed.. The short time between naloxone administration and the occurrence of complications, as well as the type of complications, are strong evidence of a causal link. In 1000 clinically diagnosed intoxications with heroin or heroin mixtures, from 4 to 30 serious complications can be expected. Such a high incidence of complications is unacceptable and could theoretically be reduced by artificial respiration with a bag valve device (hyperventilation) as well as by administering naloxone in minimal divided doses, injected slowly.

Topics: Adolescent; Adult; Aggression; Cocaine; Confidence Intervals; Drug Overdose; Female; Heart Arrest; Heroin; Humans; Illicit Drugs; Injections, Intramuscular; Injections, Intravenous; Male; Middle Aged; Naloxone; Narcotic Antagonists; Prospective Studies; Pulmonary Edema; Seizures; Substance Abuse, Intravenous

Morphine is widely used in patients and has been reported to alter seizure threshold, but its role in the development of epilepsy is unknown. In this study, role of morphine administration in the development of epilepsy using the status epilepticus (SE) model was determined in rats.. Rats experiencing SE with lithium-pilocarpine (LiP) were randomized into four groups- saline, morphine low dose (5 mg/kg, s.c.), morphine high dose (5-20 mg/kg, s.c.), and naloxone (1 mg/kg, s.c.). Treatments were started 90 min after termination of SE and repeated twice daily for next three days. Rats were video monitored daily for 21 days to determine onset and frequency of spontaneous convulsive seizures (SS).. Morphine in low doses increased frequency of SS (1.51 ± 0.15 vs LiP 0.60 ± 0.12 seizures/rat/day, p-value = 0.0026) and seizures occurred during handling (SDH) (0.08 ± 0.02 vs LiP control 0.01 ± 0.01) (p-value = 0.0018). In high doses, no significant change in SS and SDH was found as compared to LiP. No effect of morphine on the onset of SS and percentage of rats experienced SS was found. No effect of naloxone per se was found on SS.. Morphine administration after SE does not affect epileptogenesis as no change in the onset of SS and percentage of rats experiencing SS was found. However, it might alter the susceptibility and frequency of SS. As no other study is available with a similar finding, it needs further evaluation.

Topics: Animals; Disease Models, Animal; Epilepsy; Lithium; Morphine; Naloxone; Pilocarpine; Rats; Seizures; Status Epilepticus

Topics: Abdomen; Adult; Body Packing; Female; Humans; Illicit Drugs; Naloxone; Seizures; Tomography, X-Ray Computed

Tramadol is a widely used synthetic opioid. Substantial research has previously focused on the neurological effects of this drug, while the efficacy of various treatments to reduce the associated side effects has not been well studied. This study aimed to evaluate the protective effects of naloxone, diazepam, and quercetin on tramadol overdose-induced seizure and sedation level in male rats.. The project was performed with 72 male Wistar rats with an average weight of 200-250 g. The rats were randomly assigned to eight groups. Tramadol was administered intraperitoneally at an initial dose of 25 mg/kg/day. On the 14th day, tramadol was injected at 75 mg/kg, either alone or together with naloxone, diazepam, and quercetin (acute and chronic) individually or in combination. The rats were monitored for 6 h on the last day, and the number, the duration, and the severity of seizures (using the criteria of Racine) were measured over a 6-h observation period. The sedation level was also assessed based on a 4-point criterion, ranging from 0 to 3. Data were analyzed in SPSS software using Kruskal-Wallis, Chi-square, regression analysis, and generalized estimating equation (GEE) tests. The significance level was set at P < 0.05.. The naloxone-diazepam combination reduced the number, severity, and cumulative duration of seizures compared to tramadol use alone and reduced the number of higher-intensity seizures (level 3, 4) to a greater extent than other treatments. Naloxone alone reduced the number and duration of seizures but increased the number of mild seizures (level 2). Diazepam decreased the severity and duration of seizures. However, it increased the number of mild seizures (level 2). In comparison with the tramadol alone group, the acute quercetin group exhibited higher numbers of mild (level 2) and moderate (level 3) seizures. Chronic quercetin administration significantly increased the number of mild seizures. In the GEE model, all groups had higher sedation levels than the saline only group (P < 0.001). None of the protocols had a significant effect on sedation levels compared to the tramadol group.. The combined administration of naloxone and diazepam in acute-on-chronic tramadol poisoning can effectively reduce most seizure variables compared to tramadol use alone. However, none of the treatments improved sedation levels.

Topics: Animals; Diazepam; Male; Naloxone; Quercetin; Rats; Rats, Wistar; Seizures; Tramadol

We have previously demonstrated that kindling of the nucleus accumbens (NAc) induced psychosis relevant behaviors only after one, but not after five, stage-5 seizures, suggesting that five stage-5 NAc-evoked seizures antagonized psychosis relevant behaviors in rats. We hypothesized that brain opioid receptors are responsible for seizure-induced reduction of psychosis relevant behaviors in NAc kindled rats. Rats received NAc kindling until a stage-4 seizure was induced, after which naloxone, a non-specific opioid receptor antagonist, at dose of 1 or 10 mg/kg i.p., or saline (0.3 mL) i.p., was injected 15 min before each kindled seizure. Duration of afterdischarge (AD) was not significantly different among naloxone- and saline-treated groups. However, duration of postictal behavioral depression induced by a stage-5 seizure was significantly shorter in 10 mg/kg naloxone-treated than saline-treated rats, for long (>36 s) AD duration. When tested 3-4 days after five stage-5 seizures, 10 mg/kg naloxone-treated rats, as compared to saline-treated rats, showed a statistically significant loss of gating of hippocampal auditory evoked potentials, and significant reduction of startle response amplitude, but non-significant differences in prepulse inhibition and methamphetamine-induced locomotion. It is inferred that stage-5 seizures, by releasing endogenous opiates, contribute to postictal behavioral depression, and some long-term seizure-induced antipsychotic effects.

Topics: Animals; Behavior, Animal; Evoked Potentials, Auditory; Hippocampus; Locomotion; Male; Methamphetamine; Motor Activity; Naloxone; Narcotic Antagonists; Nucleus Accumbens; Opiate Alkaloids; Rats, Long-Evans; Reflex, Startle; Seizures

Topics: Causality; Drug Overdose; Humans; Naloxone; Registries; Seizures; Tramadol

Topics: Causality; Humans; Naloxone; Registries; Seizures; Tramadol

Topics: Causality; Humans; Naloxone; Registries; Seizures; Tramadol

Since the banning of dextropropoxyphene from the market, overdoses, and fatalities attributed to tramadol, a WHO step-2 opioid analgesic, have increased markedly. Tramadol overdose results not only in central nervous system (CNS) depression attributed to its opioid properties but also in seizures, possibly related to non-opioidergic pathways, thus questioning the efficiency of naloxone to reverse tramadol-induced CNS toxicity.. To investigate the most efficient antidote to reverse tramadol-induced seizures and respiratory depression in overdose.. Sprague-Dawley rats overdosed with 75 mg/kg intraperitoneal (IP) tramadol were randomized into four groups to receive solvent (control group), diazepam (1.77 mg/kg IP), naloxone (2 mg/kg intravenous bolus followed by 4 mg/kg/h infusion), and diazepam/naloxone combination. Sedation depth, temperature, number of seizures, and intensity, whole-body plethysmography parameters and electroencephalography activity were measured.. Naloxone reversed tramadol-induced respiratory depression (p < .05) but significantly increased seizures (p < .01) and prolonged their occurrence time. Diazepam abolished seizures but significantly deepened rat sedation (p < .05) without improving ventilation. Diazepam/naloxone combination completely abolished seizures, significantly improved rat ventilation by reducing inspiratory time (p < .05) but did not worsen sedation. None of these treatments significantly modified rat temperature.. Diazepam/naloxone combination is the most efficient antidote to reverse tramadol-induced CNS toxicity in the rat.

Topics: Analgesics, Opioid; Animals; Antidotes; Drug Overdose; Naloxone; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency; Seizures; Tramadol

Dextromethorphan (DM) is a dextrorotatory isomer of levorphanol, a typical morphine-like opioid. When administered at supra-antitussive doses, DM produces psychotoxic and neurotoxic effects in humans. Although DM abuse has been well-documented, few studies have examined the effects of high-dose DM. The present study aimed to explore the effects of a single high dose of DM on mortality and seizure occurrence. After intraperitoneal administration with a high dose of DM (80mg/kg), Sprague-Dawley rats showed increased seizure occurrence and intensity. Hippocampal expression levels of N-methyl-d-aspartate (NMDA) receptor subunits (GluN1

Topics: Animals; Antitussive Agents; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

This study investigated the anticonvulsant activity of Citrullus colocynthis fruit extract used traditionally in the treatment of convulsion. Albino mice were pretreated with extract in different doses (10, 25, 50, and 100 mg/kg), prior to injection of pentylenetetrazole. Animals received pretreatments with naloxone and flumazenil to further clarify the mechanisms of anticonvulsant action. The total flavonoid content of Citrullus colocynthis extract was also determined. Citrullus colocynthis hydroalcoholic extract with doses 25 and 50 mg/kg prolonged the onset of seizures and decreased the duration compared with control group. Pretreatment by flumazenil could inhibit the effect of Citrullus colocynthis on latency of seizure to some extent and administration of naloxone significantly inhibited changes in latency and duration of seizure produced by Citrullus colocynthis This study showed that Citrullus colocynthis has significant anticonvulsant effect in pentylenetetrazole-induced seizures in mice, and these effects may be related to its effect on γ-aminobutyric acid-ergic and opioid systems. These results confirmed the traditional use of Citrullus colocynthis in Iranian traditional medicine.

Topics: Animals; Anticonvulsants; Benzodiazepines; Citrullus colocynthis; Flavonoids; Flumazenil; Fruit; Herb-Drug Interactions; Male; Medicine, Arabic; Mice; Naloxone; Pentylenetetrazole; Plant Extracts; Receptors, Opioid; Seizures

Treatment of depression, a common comorbidity in patients with epilepsy, is restricted as certain antidepressants are considered to be proconvulsants. In contrast, anticonvulsant effects have been reported with some antidepressants. In the present study, the effect of tianeptine, an antidepressant, was evaluated against pentylenetetrazole (PTZ)-induced seizures, cognitive impairment and oxidative stress in rats. Tianeptine was administered in three doses (20, 40 and 80 mg/kg) 30 min before PTZ (60 mg/kg, intraperitoneally). MK801, an N-methyl-D-aspartate antagonist, and naloxone, an opioid receptor antagonist, were administered with tianeptine to evaluate the involvement of N-methyl-D-aspartate and opioid receptors, respectively. Morris water maze, elevated plus maze and passive avoidance tests were performed for behavioural assessment. Brain malondialdehyde and reduced glutathione levels were estimated as markers of oxidative stress. Tianeptine showed dose-dependent protection against PTZ seizures. Coadministration of tianeptine with MK801 potentiated the anticonvulsant effect of tianeptine. The protective effect of tianeptine against PTZ seizures was mitigated when tianeptine was administered with naloxone. Impairment of learning and memory by PTZ was prevented by tianeptine. Tianeptine also attenuated the seizure-induced increased oxidative stress. Thus, tianeptine showed an anticonvulsant effect along with amelioration of seizure-induced cognitive impairment and oxidative stress. Hence, tianeptine could be a useful drug in epileptic patients with depression, with the advantage of having both antidepressant and antiepileptic effects.

Topics: Animals; Anticonvulsants; Antidepressive Agents, Tricyclic; Avoidance Learning; Behavior, Animal; Cognitive Dysfunction; Dizocilpine Maleate; Dose-Response Relationship, Drug; Glutathione; Male; Malondialdehyde; Maze Learning; Naloxone; Oxidative Stress; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Thiazepines

Piperine, is the major active principal of black pepper. In traditional medicine, black pepper has been used as an analgesic, anti-inflammatory agent and in the treatment of epilepsy. This study was conducted to evaluate the in vivo analgesic and anticonvulsant effects of piperine in mice. The analgesic and anticonvulsant effects of piperine were studied in mice using acetic acid-induced writhing, tail flick assay, pentylenetetrazole (PTZ)- and picrotoxin (PIC)-induced seizures models. The intraperitoneal (i.p.) administration of piperine (30, 50 and 70 mg/kg) significantly inhibited (P<0.01) the acetic acid-induced writhing in mice, similar to the effect of indomethacin (20 mg/kg i.p.). In the tail flick assay, piperine (30 and 50 mg/kg, i.p.) and morphine (5 mg/kg, i.p.) caused a significant increase (P<0.01) in the reaction time of mice. Pre-treatment of animals with naloxone (5 mg/kg i.p.), reversed the analgesic effects of both piperine and morphine in the tail flick assay. Piperine (30, 50 and 70 mg/kg, i.p.) and standard drugs, valproic acid (200 mg/kg, i.p.), carbamazepine (30 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) significantly (P<0.01) delayed the onset of PTZ-and PIC-induced seizures in mice. These findings indicate that piperine exhibits analgesic and anticonvulsant effects possibly mediated via opioid and GABA-ergic pathways respectively. Moreover, piperine being the main constituent of black pepper, may be contributing factor in the medicinal uses of black pepper in pain and epilepsy.

Topics: Acetic Acid; Alkaloids; Analgesics; Animals; Anticonvulsants; Benzodioxoles; Hot Temperature; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Pentylenetetrazole; Picrotoxin; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Seizures

The aim of the present work was to investigate the involvement of the μ1-endogenous opioid peptide receptor-mediated system in post-ictal antinociception.. Antinociceptive responses were determined by the tail-flick test after pre-treatment with the selective μ1-opioid receptor antagonist naloxonazine, peripherally or centrally administered at different doses.. Peripheral subchronic (24 h) pre-treatment with naloxonazine antagonised the antinociception elicited by tonic-clonic seizures. Acute (10 min) pre-treatment, however, did not have the same effect. In addition, microinjections of naloxonazine into the central, dorsal cortical and external cortical nuclei of the inferior colliculus antagonised tonic-clonic seizure-induced antinociception. Neither acute (10-min) peripheral pre-treatment with naloxonazine nor subchronic intramesencephalic blockade of μ1-opioid receptors resulted in consistent statistically significant differences in the severity of tonic-clonic seizures shown by Racine's index (1972), although the intracollicular specific antagonism of μ1-opioid receptor decreased the duration of seizures.. μ1-Opioid receptors and the inferior colliculus have been implicated in several endogenous opioid peptide-mediated responses such as antinociception and convulsion. The present findings suggest the involvement of μ1-opiate receptors of central and pericentral nuclei of the inferior colliculus in the modulation of tonic-clonic seizures and in the organisation of post-ictal antinociception.

Topics: Animals; Inferior Colliculi; Male; Naloxone; Opioid Peptides; Pentylenetetrazole; Rats; Rats, Wistar; Receptors, Opioid, mu; Seizures; Synaptic Transmission

This study was designed to investigate the role of opioid receptors, gamma-aminobutyric acid (GABA) receptors, mast cells and histamine receptors (H(1) subtype) in the seizurogenic effect of amisulpride on mice. A single injection of amisulpride (180 mg/kg) was employed to evaluate the seizurogenicity of the drug in mice. Seizures were assessed in terms of a composite seizure severity score (SSS), time of the onset of straub-like tail, onset of jerky movements of whole body, convulsions and death. Amisulpride administration (180 mg/kg) induced a significant pro-convulsant effect in mice as measured in terms of the SSS (21.12 ± 2.71) and a significant decrease in the time latency of the onset of straub-like tail (132.45 ± 12.31), jerky movements of whole body (153.28 ± 14.12), convulsions (184.97 ± 13.11) and death (100%). Moreover, prior administration of naloxone, cetrizine, sodium cromoglycate and gabapentin, respectively, attenuated this seizurogenic activity that amisulpride exerted on mice (p < 0.05). Therefore, it may be suggested that amisulpride exerts a seizurogenic effect on mice possibly via an opioid receptor activation-dependent release of histamine from the mast cells and a simultaneous inhibition of GABA release.

Topics: Amines; Amisulpride; Analysis of Variance; Animals; Anti-Asthmatic Agents; Cromolyn Sodium; Cyclohexanecarboxylic Acids; Gabapentin; gamma-Aminobutyric Acid; Male; Mice; Mice, Inbred Strains; Naloxone; Receptors, GABA; Receptors, Histamine H1; Receptors, Opioid; Seizures; Sulpiride

The aim of this study was to investigate the capacity of the host dendrimer DAB-Am-16 as a drug carrier to reduce the time required for the encapsulated naloxonaxine to establish an irreversible covalent bond with μ(1)-opioid receptor (resulting in a pharmacologically selective effect). The efficacy of dendrimer-naloxonazine nanocomplex (DNC) was studied in antinociception induced by convulsions elicited by intraperitoneal (IP) administration of pentylenetetrazole, and analgesia was measured by the tail-flick test. We found that animals showed increased tail-flick latencies following convulsions. Furthermore, acute pre-treatment (10 minutes) with DNC, but not with naloxonazine alone, antagonized post-ictal analgesia in comparison with control pre-treatment. However, naloxonazine treatment 24 hours before PTZ decreased post-ictal antinociception, but DNC failed to antagonize tonic-clonic seizure-induced analgesia. In addition, according to Racine's index of seizure severity, naloxonazine, DAB-Am-16 dendrimer or DNC did not influence seizure severity when administered either 10 minutes or 24 hours before PTZ.. This study characterizes the effect of a dendrimer-naloxonazine complex on μ1 receptor-mediated post-ictal antinociception in an animal model of seizure disorder.

Topics: Analgesia; Animals; Dendrimers; Drug Carriers; Male; Naloxone; Narcotic Antagonists; Pentylenetetrazole; Polypropylenes; Rats; Rats, Wistar; Receptors, Opioid, mu; Seizures

Postictal movement dysfunction is a common symptom in patients with epilepsy. We investigated the involvement of opioid receptors in the nucleus accumbens (NAC) in amygdaloid kindling-induced postictal decrease in locomotion (PDL) in rats. Seizures were induced by daily electrical stimulation of the basolateral amygdala until four consecutive stage 5 seizures were elicited. Locomotion was quantified before and after infusion of an opioid receptor antagonist or saline into the NAC. Whereas PDL was induced after a stage 5 seizure in saline-infused rats, pre-infusion of the mu opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP, 5 microg/1 microL/side) into the NAC prevented PDL. Pre-infusion of delta (naltrindole, 30 microg/1 microL/side), kappa (nor-binaltorphimine, 1.8 microg/1 microL/side), or nonselective (naloxone, 10 microg/1 microL/side) opioid receptor antagonists did not block PDL, but late postictal hyperactivity was blocked by naltrindole. None of the antagonists affected amygdaloid evoked afterdischarge duration. It is suggested that mu opioid receptors in the NAC participate in amygdaloid seizure-induced PDL without affecting seizure duration.

Topics: Amygdala; Animals; Epilepsy; Kindling, Neurologic; Locomotion; Male; Naloxone; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Rats; Rats, Long-Evans; Receptors, Opioid, mu; Seizures

In the present study, the effects of tramadol on pentylenetetrazole (PTZ)-induced seizures and involvement of nitric oxide (NO) were assessed in mice. To determine the threshold for clonic seizures, PTZ was administered intravenously. Tramadol was administered intraperitoneally (0.5-50mg/kg) 30 minutes prior to induction of seizures. The effects of the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 0.5, 1, 5, and 10mg/kg), the nitric oxide precursor L-arginine (10, 30, and 60 mg/kg), and the nonspecific opioid receptor antagonist naloxone (0.1, 0.5, 1, and 5mg/kg) on the anticonvulsant effect of tramadol were investigated. Administration of tramadol (1mg/kg) increased the threshold for seizures induced with PTZ in a monophasic, dose-independent, and time-dependent manner. Acute administration of L-NAME (5 and 10mg/kg) inhibited the anticonvulsant effect of tramadol (1mg/kg), whereas L-arginine, in the noneffective dose range (30 and 60 mg/kg), potentiated the seizure threshold when co-administered with a subeffective dose of tramadol (0.5mg/kg). Naloxone partially and dose-independently antagonized the anticonvulsant effect of tramadol (1mg/kg). These results indicate that the anticonvulsant effect of tramadol is mediated by the nitric oxide pathway and also by classic opioid receptors.

Topics: Analysis of Variance; Animals; Anticonvulsants; Arginine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Male; Mice; Mice, Inbred Strains; Naloxone; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pentylenetetrazole; Seizures; Signal Transduction; Time Factors; Tramadol

Chemical-induced seizures up-regulated brain-derived neurotrophic factor (BDNF) mRNA expression. Intracerebroventricular (i.c.v.) administration of endogenous opioids preferentially activating mu opioid receptor (MOR) could also increase BDNF mRNA expression. The aim of this study was to determine to what extent i.c.v. administration of synthetic MOR-selective agonists in rats can modulate both seizure activity and up-regulation of BDNF mRNA expression. Effects and potencies of i.c.v. administration of morphine and [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO), were directly investigated by scoring behavioral seizures and measuring BDNF mRNA expression. In addition, effects of the opioid receptor antagonist naloxone and antiepileptic drugs, diazepam, phenobarbital, and valproate, on i.c.v. MOR agonist-induced behavioral seizures and up-regulation of BDNF mRNA expression were determined. A single i.c.v. administration of morphine (10-100 microg) or DAMGO (0.15-1.5 microg) dose-dependently elicited behavioral seizures and increased BDNF mRNA expression in the widespread brain regions. However, s.c. administration of MOR agonists neither produced behavioral seizures nor increased BDNF mRNA expression. Pretreatment with naloxone 1 mg/kg significantly reduced behavioral seizure scores and the up-regulation of BDNF mRNA expression elicited by i.c.v. morphine or DAMGO. Similarly, diazepam 10 mg/kg and phenobarbital 40 mg/kg significantly blocked i.c.v. MOR agonist-induced actions. Pretreatment with valproate 300 mg/kg only attenuated behavioral seizures, but it did not affect morphine-induced increase of BDNF mRNA expression. This study provides supporting evidence that seizure activity plays an important role in the up-regulation of BDNF mRNA expression elicited by central MOR activation and that decreased inhibitory action of GABAergic system through the modulation on GABA receptor synaptic function by central MOR activation is involved in its regulation of BDNF mRNA expression.

Topics: Animals; Anticonvulsants; Brain-Derived Neurotrophic Factor; Drug Synergism; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Injections, Intraventricular; Male; Morphine; Naloxone; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; RNA, Messenger; Seizures; Up-Regulation

To study the behavioral depression induced by a generalized limbic seizure and by an opioid. The hypothesis that an opioid fentanyl and an amygdala-evoked seizure induced behavioral depression through the nucleus accumbens was tested.. The behavioral depression induced by an amygdala-kindled seizure was studied in fully kindled rats, with or without prior injection of fentanyl (0.05 mg/kg, s.c.). Local infusion of a nonspecific opioid antagonist, naloxone, or saline, was made bilaterally in the nucleus accumbens. The durations of loss of righting reflex (LORR), loss of tail-pinch response, and catalepsy were assessed.. Fentanyl induced an LORR following a generalized kindled seizure. The combination of fentanyl and a generalized seizure, as compared to fentanyl alone or a generalized seizure alone, resulted in a prolonged duration of LORR, catalepsy, and loss of tail pinch response. Infusion of naloxone as compared to saline in the nucleus accumbens reduced the duration of catalepsy and LORR induced by fentanyl, with or without a generalized seizure.. Postictal depression that follows a generalized kindled seizure enhanced the behavioral effects of the opioid fentanyl. Network synaptic depression induced by the seizure acted synergistically with fentanyl to produce analgesia, catalepsy, and LORR, in part through the nucleus accumbens.

Topics: Amygdala; Analysis of Variance; Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Electric Stimulation; Electroencephalography; Fentanyl; Functional Laterality; Kindling, Neurologic; Male; Naloxone; Narcotic Antagonists; Narcotics; Nucleus Accumbens; Rats; Rats, Long-Evans; Reflex; Seizures; Statistics, Nonparametric

The present study has been designed to pharmacologically investigate the role of opioid and gamma-aminobutyric acid receptors on the seizurogenic effect of tramadol. A single injection of pentylenetetrazole (80 mg/kg) was used to elicit seizure activity in mice. Seizures were assessed in terms of the time latency of the onset of Straub's tail phenomenon, onset of jerky movements of whole body, convulsions and death. Tramadol administration (50 mg/kg) caused a marked increase in seizurogenic activity of pentylenetetrazole as measured in terms of a significant decrease in the time latency of the onset of Straub's tail phenomenon, jerky movements of whole body, convulsions and death. Moreover, prior administration of naloxone (2 mg/kg) and gabapentin (25 mg/kg), respectively, attenuated the seizurogenic activity that tramadol exerted on pentylenetetrazole-treated mice. Furthermore, prior administration of naloxone (2 mg/kg) and gabapentin (25 mg/kg), respectively, also attenuated the seizurogenic activity exerted by tramadol per se. Therefore, it is suggested that tramadol exerts a seizurogenic effect on mice possibly via an opioid-dependent gamma-aminobutyric acid inhibitory pathway.

Topics: Amines; Analgesics, Opioid; Animals; Cyclohexanecarboxylic Acids; GABA Agents; Gabapentin; gamma-Aminobutyric Acid; Mice; Mice, Inbred Strains; Naloxone; Narcotic Antagonists; Pentylenetetrazole; Receptors, GABA; Receptors, Opioid; Seizures; Tramadol

To investigate the anticonvulsant activity of root bark extract of Carissa edulis.. The median lethal dose (LD(50)) of Carissa edulis extract was determined using Lork's method (1983). The anticonvulsant activity of the extract was assessed in pentylenetetrazole (PTZ)-induced convulsion in mice and maximal electroshock test (MEST) in chicks, with benzodiazepine and phenytoin as standard drugs, respectively. While mechanistic studies were conducted using both flumazenil, a GABA(A)-benzodiazepine receptor complex site antagonist and naloxone a non-specific opioid receptor antagonist.. The median lethal dose (LD(50)) of Carissa edulis was 282.8mg/kg and over 5000mg/kg following intraperitoneal and oral administration, respectively. Carissa edulis produced 40% and 20% protection against convulsion at 5 and 20mg/kg, respectively, compared with 100% protection with benzodiazepine. The mean onset and percentage protection against convulsion in Carissa edulis extract-treated mice were reduced by flumazenil and naloxone. Carissa edulis exhibited dose-dependent inhibition of the convulsion induced by MEST with 20mg/kg providing 90% protection while phenytoin (20mg/kg) produced 100% protection.. These results suggest that Carissa edulis possesses biologically active constituent(s) that have anticonvulsant activity which supports the ethnomedicinal claims of the use of the plant in the management of epilepsy.

Topics: Administration, Oral; Animals; Anticonvulsants; Apocynaceae; Chickens; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Flumazenil; Injections, Intraperitoneal; Lethal Dose 50; Male; Mice; Naloxone; Phenytoin; Plant Bark; Plant Extracts; Plant Roots; Seizures; Toxicity Tests, Acute

Tramadol is one of the most widely used centrally acting analgesics worldwide. Because of its multimodal analgesic mechanism (opioid plus nonopioid), the adverse effects profile of tramadol, similar to its analgesic profile, can be atypical compared with single-mechanism opioid analgesics. The comparison is often favorable (e.g., less respiratory depression or abuse), but it is sometimes cited as unfavorable in regard to seizure potential. As part of a broader study of this analgesic, we compared seizure induction in mice produced by administration of tramadol, the enantiomers and metabolites [M1 (O-desmethyl tramadol), M2 (N-desmethyl tramadol), M3 (N,N-didesmethyl tramadol), M4 (O,N,N-tridesmethyl tramadol), and M5 (O,N-didesmethyl tramadol)] of tramadol, and opioid and nonopioid reference compounds. We found that tramadol, its enantiomers, and M1 to M5 metabolites were of intermediate potency in this endpoint (on either a milligram per kilogram or millimole per kilogram basis). The SD50 (estimated dose required to induce seizures in 50% of test group) of tramadol to antinociceptive ED50 ratio was almost identical to that of codeine. The enantiomers of tramadol were about equipotent to tramadol on this endpoint. The M1 to M5 metabolites (and M1 enantiomers) of tramadol were less potent than tramadol. The relative potency of tramadol to opioids was not altered by quinidine (an inhibitor of CYP4502D6), noxious stimulus (48 degrees C hot-plate), multiple dosing, or in reserpinized mice. Tramadol seizures were increased by naloxone, principally at high tramadol doses and due to an effect on the (-)enantiomer that overcame the opposite effect on the (+)enantiomer. No synergistic effect on seizure induction was observed between concomitant tramadol and codeine or morphine.

Topics: Analgesics, Opioid; Animals; Codeine; Cytochrome P-450 CYP2D6 Inhibitors; Drug Interactions; Hot Temperature; Male; Mice; Mice, Inbred Strains; Morphine; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Quinidine; Reserpine; Seizures; Stereoisomerism; Tramadol

Opioid systems in hippocampus regulate excitability and kappa opioids have a role in anticonvulsant protection, but their mechanisms of action are incompletely understood. We examined the ability of opioid and nonopioid agents with overlapping ionic mechanisms and actions similar to kappa opioid agonists, to block seizures in rat models of encephalitis due to Borna Disease virus and Herpes Simplex Virus Type-1. Naltrindole, a delta antagonist and thus a kappa opioid sparing agent, (10 mg/kg s.c.) blocked spontaneous and naloxone (opioid antagonist)-induced seizures in the models, but produced somatic signs similar to opioid withdrawal. Given that delta antagonists as well as kappa opioid agonists in hippocampus enhance potassium M currents (I(M)), we tested the effect of the I(M) augmenter flupirtine. Flupirtine (20 mg/kg i.p.) prevented seizures in Borna and herpes infected rats, without signs of withdrawal, hypotonia or sedation. The results support the efficacy of opioid and nonopioid drugs in modulating naloxone-induced seizures in critical illness due to viral encephalitis and by analogy, opioid withdrawal seizures.

Topics: Aminopyridines; Analgesics; Animals; Anticonvulsants; Borna Disease; Encephalitis, Viral; Herpes Simplex; Herpesvirus 1, Human; Male; Naloxone; Naltrexone; Narcotic Antagonists; Potassium; Rats; Rats, Inbred Lew; Receptors, Opioid, delta; Seizures; Substance Withdrawal Syndrome

Topics: Accidents; Administration, Cutaneous; Analgesics, Opioid; Antihypertensive Agents; Clonidine; Coma; Drug Overdose; Emergency Treatment; Fentanyl; Humans; Infant; Naloxone; Narcotic Antagonists; Patient Education as Topic; Seizures; Self Administration

Epilepsy remains a major medical problem of unknown aetiology. Potentially, viruses can be environmental triggers for development of seizures in genetically vulnerable individuals. An estimated half of encephalitis patients experience seizures and approximately 4% develop status epilepticus. Epilepsy vulnerability has been associated with a dynorphin promoter region polymorphism or low dynorphin expression genotype, in man. In animals, the dynorphin system in the hippocampus is known to regulate excitability. The present study was designed to test the hypothesis that reduced dynorphin expression in the dentate gyrus of hippocampus due to periadolescent virus exposure leads to epileptic responses. Encephalitis produced by the neurotropic Borna disease virus in the rat caused epileptic responses and dynorphin to disappear via dentate granule cell loss, failed neurogenesis and poor survival of new neurons. Kappa opioid (dynorphin) agonists prevented the behavioural and electroencephalographic seizures produced by convulsant compounds, and these effects were associated with an absence of dynorphin from the dentate gyrus granule cell layer and upregulation of enkephalin in CA1 interneurons, thus reproducing a neurochemical marker of epilepsy, namely low dynorphin tone. A key role for kappa opioids in anticonvulsant protection provides a framework for exploration of viral and other insults that increase seizure vulnerability and may provide insights into potential interventions for treatment of epilepsy.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Blotting, Northern; Borna Disease; Cell Survival; Disease Models, Animal; Dynorphins; Electroencephalography; Encephalitis, Viral; Enkephalins; Hippocampus; Male; Naloxone; Narcotic Antagonists; Neurons; Rats; Rats, Inbred Lew; Receptors, Opioid, kappa; Seizures

This study was undertaken to examine the effect of fentanyl on lidocaine-induced convulsions in mice. Seventy-five male mice were used and divided into five groups, 15 in each. Convulsions were obtained by lidocaine injection subcutaneously (150 mg/kg), in a dose volume of 0.1 ml/10 g body weight over the upper back. The five groups were: (a) control group: pretreated with normal saline; (b) F50 group: pretreated with fentanyl 50 microg/kg; (c) F100 group: pretreated with fentanyl 100 microg/kg; (d) F200 group: pretreated with fentanyl 200 microg/kg, and (e) F100+N group: pretreated with fentanyl 100 mug/kg plus naloxone 1 mg/kg. The pretreatments were given intraperitoneally (i.p.) 5 min prior to lidocaine injection. After lidocaine injection, the latency to the onset of generalized convulsions was observed for 12 min and recorded. The severity of convulsions was assessed and scored as 1 = mild, 2 = moderate, and 3 = severe. The recovery or death of the mice were also recorded. Student's t, Mann-Whitney U, and Fisher's exact tests were used to analyze the data. Compared with the control group (431.7 +/- 37.3 s), the latencies of onset of convulsions in the fentanyl groups were dose-dependently decreased (F50: 331.0 +/- 37.1 s; F100: 240.3 +/- 28.6 s, p < 0.001; F200: 188.7 +/- 19.4 s, p < 0.001), and the decreased latency was reversed by naloxone (F100+N: 412.9 +/- 34.1 s). Compared with the control group (1.13 +/- 0.19), the severities of convulsions in the fentanyl groups were also increased in a dose-dependent manner (F50: 1.47 +/- 0.19; F100: 1.93 +/- 0.21, p < 0.05; F200: 2.46 +/- 0.17, p < 0.001). Similarly, the increased severity was reversed by naloxone (F100+N: 1.33 +/- 0.16). There was no death in the control and naloxone-treated groups. The incidences of death were 2/15 in F50 group, 5/15 in F100 group, and 7/15 in the F200 group (p < 0.05). The results of this study demonstrated that fentanyl potentiates the lidocaine-induced convulsions in a dose-dependent manner in mice, and this effect may be mediated by an opioid mechanism.

Topics: Animals; Dose-Response Relationship, Drug; Drug Synergism; Fentanyl; Injections, Intraperitoneal; Lidocaine; Male; Mice; Mice, Inbred ICR; Naloxone; Narcotic Antagonists; Narcotics; Preanesthetic Medication; Seizures

Dyskinesias and seizures are both medically refractory disorders for which cannabinoid-based treatments have shown early promise as primary or adjunctive therapy. Using the Borna disease (BD) virus rat, an animal model of viral encephalopathy with spontaneous hyperkinetic movements and seizure susceptibility, we identified a key role for endocannabinoids in the maintenance of a balanced tone of activity in extrapyramidal and limbic circuits. BD rats showed significant elevations of the endocannabinoid anandamide in subthalamic nucleus, a relay nucleus compromised in hyperkinetic disorders. While direct and indirect cannabinoid agonists had limited motor effects in BD rats, abrupt reductions of endocannabinoid tone by the CB1 antagonist SR141716A (0.3 mg/kg, i.p.) caused seizures characterized by myoclonic jerks time-locked to periodic spike/sharp wave discharges on hippocampal electroencephalography. The general opiate antagonist naloxone (NLX) (1 mg/kg, s.c.), another pharmacologic treatment with potential efficacy in dyskinesias or L-DOPA motor complications, produced similar seizures. No changes in anandamide levels in hippocampus and amygdala were found in convulsing NLX-treated BD rats. In contrast, NLX significantly increased anandamide levels in the same areas of normal uninfected animals, possibly protecting against seizures. Pretreatment with the anandamide transport blocker AM404 (20 mg/kg, i.p.) prevented NLX-induced seizures. These findings are consistent with an anticonvulsant role for endocannabinoids, counteracting aberrant firing produced by convulsive agents, and with a functional or reciprocal relation between opioid and cannabinoid tone with respect to limbic convulsive phenomena.

Topics: Animals; Anticonvulsants; Arachidonic Acids; Basal Ganglia; Borna Disease; Cannabinoid Receptor Modulators; Convulsants; Disease Models, Animal; Endocannabinoids; Limbic System; Male; Movement Disorders; Naloxone; Narcotic Antagonists; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Inbred Lew; Receptor, Cannabinoid, CB1; Rimonabant; Seizures

To evaluate the effect of low dose naloxone on remote seizure susceptibility after repeated febrile seizures(FS) in developing age.. Warm water induced rat FS model was developed in this study. Forty-nine SD rats were randomly divided into two groups: normal control group(n=10) and hyperthermic seizure group (n=39). The latter was further divided into FS control group (n=13) and naloxone-treated group (n=26). The dose of naloxone was different in the two naloxone-treated groups (13/each group). One group dose was 1 mg/kg, and the other 2 mg/kg. Each rat of hyperthermic seizure groups was induced to have 7 febrile seizures at the interval of 1 day. The rats were weighed and injected intraperitoneally with naloxone once the FS occurred in naloxone-treated group, while the rats of other groups were injected with 0.9% sodium chloride. After the seventh stimulation, all rats were left un-stimulated for 2 months, then re-stimulated. Re-stimulated seizure incidence rate, seizure duration and seizure grade in different groups were observed and compared with each other. Hippocampal mossy fiber sprouting was detected by Timm stain.. In naloxone-treated group, the rats' seizure duration and seizure grade [(5.66+/-2.78) min, (2.97+/-1.18)] significantly decreased (t=5.035, P<0.01; t=3.343, P<0.01) compared with those in FS control group [(21.18+/-4.06) min, (4.54+/-0.78)], although no significant gap was observed on seizure incidence rate(57.7%,84.6% respectively) and seizure latency between them. In non-treated group, in which two rats developed status epilepsy, the incident rate of the fifth grade seizure was 69.3%, much higher than 19.3% of naloxone treated group. Timm-stain pattern showed that the straining in the IML (inner molecular layer) of treated group rats was much lighter than that of non-treated group [(2.33+/-1.03), (0.92+/-0.79), P<0.01].. Low dose naloxone used on naive rat with repeated febrile seizures can efficiently decrease the seizure susceptibility in the mature period and lighten the neural damage by twice-hit seizure in the mature period as well.

Topics: Animals; Dentate Gyrus; Disease Susceptibility; Immunohistochemistry; Male; Mossy Fibers, Hippocampal; Naloxone; Rats; Rats, Sprague-Dawley; Seizures

An increasing and serious heroin overdose problem in Oslo has mandated the increasing out-of-hospital use of naloxone administered by paramedics. The aim of this study was to determine the frequencies and characteristics of adverse events related to this out-of-hospital administration by paramedics.. A one-year prospective observational study from February 1998 to January 1999 was performed in patients suspected to be acutely overdosed by an opioid. A total of 1192 episodes treated with naloxone administered by the Emergency Medical Service system in Oslo, were included. The main outcome variable was adverse events observed immediately after the administration of naloxone.. The mean age of patients included was 32.6 years, and 77% were men. Adverse events suspected to be related to naloxone treatment were reported in 45% of episodes. The most common adverse events were related to opioid withdrawal (33%) such as gastrointestinal disorders, aggressiveness, tachycardia, shivering, sweating and tremor. Cases of confusion/restlessness (32%) might be related either to opioid withdrawal or to the effect of the heroin in combination with other drugs. Headache and seizures (25%) were probably related to hypoxia. Most events were non-serious. In three episodes (0.3%) the patients were hospitalized because of adverse events.. Although adverse events were common among patients treated for opioid overdose in an out-of-hospital setting, serious complications were rare. Out-of-hospital naloxone treatment by paramedics seems to save several lives a year without a high risk of serious complications.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Confusion; Drug Overdose; Emergency Medical Services; Female; Headache; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Narcotics; Nausea; Norway; Prospective Studies; Seizures; Substance-Related Disorders; Tachycardia; Tremor; Vomiting

There has been much debate regarding the potential influence of stress on epilepsy. Many studies have reported that stress can affect seizure susceptibility through eliciting either proconvulsant or anticonvulsant effects within the nervous system. In this study, we investigated the potential anticonvulsant effect of a 10-min swim stress on convulsions induced by a single systemic injection of lithium chloride followed 4 h later with pilocarpine. Rats pretreated with lithium chloride and exposed to a 10-min swim stressor prior to pilocarpine injection displayed a significant delay to seizure onset compared to unstressed rats or rats exposed to swim stress 10 min after lithium chloride, 2 h after lithium chloride, or immediately after pilocarpine injection. We then determined whether administration of a glucocorticoid antagonist (mifepristone; 10 or 50 mg/kg), an alpha(2)-adrenergic antagonist (yohimbine; 2 or 5 mg/kg), or a nonspecific opioid blocker (naloxone; 0.2 or 1 mg/kg) could prevent the anticonvulsant effect of swim stress. Only the high dose of yohimbine was capable of inhibiting the anticonvulsant effect of swim stress on lithium-pilocarpine seizures. Our findings highlight the importance of an endogenous noradrenergic-dependent anticonvulsant system in mediating the effects of swim stress on seizures. Further studies exploring the benefits of treatments with noradrenergic acting drugs in epilepsy is well warranted.

Topics: Adrenergic alpha-Antagonists; Animals; Anticonvulsants; Lithium; Male; Mifepristone; Naloxone; Pilocarpine; Rats; Rats, Wistar; Seizures; Stress, Physiological; Swimming; Yohimbine

Central nervous system (CNS) inflammation in cases such as head trauma, infection and stroke has been associated with the occurrence of epileptic seizures. Microglia, the principal immune cells in the brain, readily become activated in response to injury, infection or inflammation. The bacterial endotoxin lipopolysaccharide (LPS) induces the activation of microglia and the production of proinflammatory factors including nitric oxide (NO) and prostaglandins (PGs). We examined the effect of LPS on seizure susceptibility of mice, by using the sensitive test, threshold of clonic seizures induced by i.v. infusion of pentylenetetrazole. LPS decreased the seizure threshold in a dose- and time-dependent manner. Pretreatment of mice with the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester or cyclooxygenase inhibitor, piroxicam or the opioid receptor antagonist, (-)-naloxone completely reversed the proconvulsant effect of LPS. These results indicate that NO, PGs and endogenous opioid peptides seem to be involved in LPS-induced decrease in seizure threshold.

Topics: Animals; Disease Susceptibility; Drug Synergism; Inflammation Mediators; Lipopolysaccharides; Male; Mice; Naloxone; NG-Nitroarginine Methyl Ester; Nitric Oxide; Piroxicam; Prostaglandins; Seizures

Acute subcutaneous administration of lower doses of morphine (0.5, 1 and 3 mg/kg) increase the threshold of seizures induced by pentylenetetrazole (PTZ) in mice, whereas higher doses of morphine (15, 30 and 60 mg/kg) have proconvulsant effects. The effect of systemic administration of nitric oxide synthase (NOS) inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-nitro-L-arginine (L-NNA) and nitric oxide synthase (NOS) L-arginine on biphasic effect of morphine was investigated. Acute administration of both L-NAME (1, 3 and 10 mg/kg) and L-NNA (1 and 10 mg/kg) as well as chronic pretreatment with L-NAME (1 and 10 mg/kg, 4 days) dose-dependently inhibited both the anticonvulsant and proconvulsant effects of morphine (1 and 30 mg/kg, respectively). The inhibition was complete for anticonvulsant effect while partial for proconvulsant effect. L-arginine at doses that did not affect seizure threshold per se (acute, 30 and 60 mg/kg; chronic, 60 mg/kg) potentiated both anticonvulsant and proconvulsant properties of less potent doses of morphine (0.5 and 15 mg/kg, respectively). The L-arginine induced potentiation of both phases of morphine effect was blocked by L-NAME (0.5-30 mg/kg). Moreover, low and per se non-effective doses of naloxone (0.1 mg/kg) and L-NAME (0.3, 0.5 or 1 mg/kg) showed additive effects in inhibiting both phases of morphine effects. These results support the involvement of L-arginine/nitric oxide pathway in the modulation of seizure threshold by morphine.

Topics: Analgesics, Opioid; Animals; Anticonvulsants; Convulsants; Dose-Response Relationship, Drug; Enzyme Inhibitors; Injections, Subcutaneous; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Seizures

Between 1987 and 1997, we chemically immobilized 597 wild sea otters (Enhydra lutris) in Alaska for the collection of biological samples or for surgical instrumentation. One drug-related sea otter fatality occurred during this time. Fentanyl in combination with diazepam produced consistent, smooth inductions with minimal need for supplemental anesthetics during procedures lasting 30-40 min. Antagonism with naltrexone or naloxone was rapid and complete, although we observed narcotic recycling in sea otters treated with naloxone. For surgical procedures, we recommend a fentanyl target dose of 0.33 mg/kg of body mass and diazepam at 0.11 mg/kg. For nonsurgical biological sample collection procedures, we recommend fentanyl at 0.22 mg/kg and diazepam at 0.07 mg/kg. We advise the use of the opioid antagonist naltrexone at a ratio of 2:1 to the total fentanyl administered during processing.

Topics: Anesthesia; Anesthetics, Combined; Anesthetics, Intravenous; Animals; Azaperone; Body Temperature; Diazepam; Female; Fentanyl; Heart Rate; Hypnotics and Sedatives; Immobilization; Logistic Models; Male; Naloxone; Naltrexone; Narcotic Antagonists; Otters; Respiration; Seizures; Time Factors; Tremor

The neural mechanisms involved in post-ictal analgesia remain to be elucidated. Pentylenetetrazol (PTZ) is used experimentally to induce seizure in animal subjects. This non-competitive antagonist blocks GABA-mediated Cl(-) flux. The aim of this work is to study the neurochemical basis of the antinociception induced by convulsions elicited by peripheral administration of PTZ (64 mg/kg). The analgesia was measured by the tail-flick test, in eight rats per group. Convulsions were followed by significant increase in the tail-flick latencies (TFL), at least for 30 min of the post-ictal period. Peripheral administration of naloxone (5 mg/kg and 10 mg/kg), atropine (1 mg/kg and 5 mg/kg), methysergide (1 mg/kg and 5 mg/kg) and ketanserine (1 mg/kg and 2 mg/kg) caused a significant decrease in the TFL in seizing animals, as compared to controls. However, while naloxone antagonized analgesia 15 and 25 min post convulsions, the other drugs caused a blockade of the post-ictal analgesia in a relatively greater period of time. These results indicate that endogenous opioids, serotonin and acetylcholine may be involved in post-ictal analgesia.

Topics: Analgesia; Animals; Atropine; Convulsants; Disease Models, Animal; Injections, Intraperitoneal; Ketanserin; Methysergide; Motor Activity; Muscarinic Antagonists; Naloxone; Narcotic Antagonists; Pain Measurement; Pentylenetetrazole; Rats; Rats, Wistar; Reaction Time; Reflex; Seizures; Serotonin Antagonists

To describe an adverse effect with intravenous codeine in a chid diagnosed with sickle cell anemia.. A seven-year-old boy with sickle cell anemia was admitted to the emergency department with severe pain unresponsive to high doses of oral acetaminophen; subsequently, intravenous codeine phosphate was administered. The patient immediately developed a tonic-clonic seizure, which was treated with intravenous diazepam and naloxone.. Seizures associated with the intravenous administration of codeine phosphate have not been extensively reported in the literature, and special precautions for using the parenteral route for this drug have been vague and limited. Because of the frequent need for acute pain control in children with sicke cell crisis, they may be exposed to this type of reaction when intravenous narcotics are administered. The need for clear guidelines regarding the drug's appropriate parenteral dosing and administration is essential.. Codeine phosphate-induced seizures are not common. The need for special instructions for its intravenous administration may prevent this type of reaction, especially in patients in need of acute pain control requiring intravenous narcotics.

Topics: Analgesics, Opioid; Anemia, Sickle Cell; Anticonvulsants; Child; Codeine; Diazepam; Humans; Injections, Intravenous; Male; Naloxone; Narcotic Antagonists; Pain; Seizures; Treatment Outcome

The postictal behavioral depression (PBD), characterized by behavioral immobility and unresponsiveness to environmental stimuli, observed after a stage 5 kindling seizure is opioid dependent. Morphine injection prolongs while naloxone and naltrexone (opioid antagonists) reduce or eliminate PBD. Opioids have clear rewarding actions that can be easily detected by place preference conditioning (PPC). In the present study, we evaluated if the opioid release after a stage 5 kindling seizure that produces PBD could induce PPC. Male rats were kindled in the medial preoptic area (MPOA), the amygdala (AMG) or insular cortex (IC). After kindling was established their initial preference in a three-compartment chamber was determined. During conditioning, subjects received a standard kindling stimuli that evoked a stage 5 seizure. At the end of the after discharge and during the PBD the animals were placed in the non-preferred chamber for 30 min. On alternate days they were placed without stimulation in the preferred chamber. At the end of conditioning the kindled groups showed a clear change of preference. This change of preference was completely blocked by injection of naloxone. These results suggest that opioid release after a stage 5 kindling seizure can induce a positive affect of sufficient intensity and duration to induce conditioning.

Topics: Amygdala; Animals; Cerebral Cortex; Conditioning, Classical; Kindling, Neurologic; Male; Naloxone; Narcotic Antagonists; Opioid Peptides; Preoptic Area; Rats; Rats, Wistar; Reward; Seizures; Spatial Behavior

Preconditioning is defined as an adaptive mechanism produced by short periods of hypoxia/ischemia, resulting in protection against subsequent ischemic insult, and development of seizures. Results of the present study demonstrate that an episode of normobar hypoxia reduces the susceptibility to convulsions induced by pentylenetetrazol (PTZ) 30 min, 24 h, as well as 4 and 7 days later. Administration of morphine showed similar effects after 24 h. Naloxone, given before ischemic preconditioning, as well as morphine, blocked the development of the protection. Administration of D-Ala-Met-enkephalin-Gly-ol (DAMGO - a selective mu-opioid receptor agonist), as well as trans-3, 4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl) cycloexilbenzeneacetamide ethane sulfonate] (U-69,593 - a selective kappa-opioid receptor agonist), mimicked the effects of hypoxic preconditioning (HPC). (-)-N-(Cyclopropylmethyl)-4,14-dimethoxymorphinan-6-one (cyprodime - a selective mu-opioid receptor antagonist, as well as nor-binaltorphimine dihydrochloride (nor-BNI - selective kappa-opioid receptors antagonist), given before HPC as well as before respective opioid receptor agonists, blocked the development of the protection. This study provides evidence that mu- and kappa-opioid receptors are involved in HPC against seizures in the brain.

Topics: Animals; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Female; Hypoxia; Ischemic Preconditioning; Mice; Morphine; Naloxone; Receptors, Opioid; Seizures

The nuclei comprising the neuronal network for audiogenic seizures (AGS) are located primarily in the brainstem. Previous studies suggested a role for the periaqueductal grey (PAG) in the AGS network. The present study evaluated this possibility in genetically-epilepsy prone rats (GEPR-9s) by examining the effects of bilateral focal microinjection of a competitive NMDA receptor antagonist (DL-2-amino-7-phosphonoheptanoic acid (AP7), 1 and 5 nmol/side), a GABA(A) agonist (gaboxedol (THIP), 10 and 15 nmol) or an opioid peptide receptor antagonist (naloxone, 5 nmol) into PAG, based on the proposed role of these receptors in PAG neurotransmission. Blockade of NMDA receptors by AP7 (both doses) or activation of GABA(A) receptors with THIP (15 nmol/side) in the PAG suppressed AGS susceptibility. Naloxone displayed a seizure-suppressant effect that was delayed and incomplete. The seizure suppressant effect of AP7 or naloxone, unlike THIP, was observed at doses that did not produce motor quiescence. These data suggest that the PAG is a requisite nucleus in the neuronal network for AGS in GEPR-9s and that GABA(A), opioid peptide and NMDA receptors in the PAG modulate AGS propagation.

Topics: 2-Amino-5-phosphonovalerate; Animals; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; GABA-A Receptor Agonists; Isoxazoles; Male; Microinjections; Naloxone; Narcotic Antagonists; Nerve Net; Periaqueductal Gray; Rats; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Seizures

To describe the association between opioid administration in the newborn period and neurologic abnormalities.. Case reports of two infants who presented with seizure activity and abnormal electroencephalograms associated with opiate administration, and reversed by naloxone.. The first was a preterm infant who developed a burst-suppression pattern on the electroencephalogram while receiving a continuous infusion of morphine and muscle paralysis. Naloxone injection during the electroencephalogram recording reversed the burst-suppression pattern. The second was a term infant receiving fentanyl infusion for pain control following surgery, who presented with motor seizure that was only partially controlled with barbiturates. An abnormal electroencephalogram recording during the opiate infusion improved with naloxone administration.. Our observations indicate a potential for neurologic abnormalities, including induction of seizure activity and electroencephalogram abnormalities, suggesting caution when opiates are used for sedation and/or pain control in the newborn period.

Topics: Brain; Electroencephalography; Female; Humans; Infant, Newborn; Male; Morphine; Naloxone; Narcotic Antagonists; Seizures

The present study was designed to investigate the pro- or anticonvulsant effect of tramadol using maximal electroshock (MES) test. An attempt was also made to determine the possible opioid receptor mechanism involved. MES seizures were induced through transauricular electrodes (60 mA, 0.2s) and the seizure severity was assessed by the duration of tonic hindlimb extensor phase. Intraperitoneal (i.p.) administration of tramadol resulted in a dose-dependent anticonvulsant action; the ED50 for the effect was 33 mg/kg. The anti-MES effect of tramadol was antagonized by the low doses (0.05 and 0.1 mg/kg, s.c.) of MR 2266, a selective kappa receptor antagonist and also by the high doses (1.0 and 5.0 mg/kg, i.p.) but not the low doses (0.1 and 0.25 mg/kg) of naloxone. The results suggest that the anti-MES effect of tramadol is mediated by kappa receptors, since MR 2266 and naloxone (in high doses) are known to block these receptors.

Topics: Animals; Anticonvulsants; Benzomorphans; Drug Interactions; Electroshock; Female; Male; Mice; Naloxone; Narcotic Antagonists; Receptors, Opioid, kappa; Seizures; Tramadol

Intraperitoneal (i.p.) administration of (+/-) pentazocine (10, 30 & 50 mg/kg), a Sigma opioid agonist, resulted in a dose dependent anticonvulsant action against maximal electroshock seizures in mice. This anticonvulsant effect of pentazocine was not antagonized by both the doses of naloxone (1 and 10 mg/kg) suggesting thereby that its anticonvulsant action is probably mediated by Sigma opiate binding sites. Its anticonvulsant effect was potentiated by both the anticonvulsant drugs viz. diazepam and diphenylhydantoin. Morphine, mu opioid agonist, on the other hand, failed to protect the animals against maximal electroshock seizures when it was given in doses of 10-40 mg/kg body wt.

Topics: Analgesics, Opioid; Animals; Anticonvulsants; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Female; Male; Mice; Mice, Inbred Strains; Naloxone; Narcotic Antagonists; Pentazocine; Seizures; Treatment Outcome

Endogenous opioids modulate processes of central excitability such as long-term potentiation and electrical kindling. Little is known about the neurochemical alterations in the interaction of the glutamatergic and opioid system in the development of pentylenetetrazol (PTZ) kindling in rats. Therefore, in the present study we investigated glutamate, DAMGO and naltrindole receptor binding, receptor protein expression by Western blot and ex vivo glutamate transmitter release in PTZ kindled rats. The specific 3H-DAMGO and -naltrindole binding to hippocampal membranes displayed no significant changes in kindled rats compared to controls. In contrast, the 3H-l-glutamate binding was significantly enhanced after completion of PTZ kindling. The expression of receptor protein for glutamate as well as the naloxone- and naltrindole-induced 3H-d-aspartate release from hippocampal slices did not alter in any case as a consequence of PTZ kindling. The PTZ induced enhancement of the glutamate binding sites in the hippocampus was downregulated to control level by natrindole treatment of rats prior to each PTZ application. Furthermore, naltrindole pretreatment of rats significantly inhibited the development of seizure susceptibility. In contrast, naloxone was not able to alter the seizure activity induced by PTZ as well as the transmitter receptor binding. The results are discussed in the light of a modulating role of delta-opioid receptors in PTZ kindling.

Topics: Animals; Convulsants; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Hippocampus; In Vitro Techniques; Kindling, Neurologic; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pentylenetetrazole; Rats; Rats, Wistar; Receptors, Glutamate; Receptors, Opioid; Seizures; Synapses

Tramadol is a novel analgesic possessing both opiate and noradrenergic effects. Its low potential for abuse suggests increasing use, but there are limited data on the toxicity in overdose.. Multicenter prospective case series. All exposures from October 1995 through August 1996 reported to seven Poison Centers were evaluated.. There were 126 cases of which 87 were tramadol alone. Of the tramadol alone cases, 51 were female (59%). Age ranged from 1 to 86 y with a mean and median of 26.8 y (SD 17.2) and 25 y, respectively. There were 15 cases of children less than 6 years old. Symptoms reported with overdose were: lethargy 26 (30%), nausea 12 (14%), tachycardia 11 (13%), agitation 9 (10%), seizures 7 (8%), 4 each (5%) of coma and hypertension, and respiratory depression 2 (2%). All seizures were brief. Naloxone reversed sedation and apnea in 4 of 8 patients. One patient experienced a seizure immediately after administration of naloxone. Other treatments were: diazepam (3 patients), and phenytoin, lorazepam and nifedipine (1 patient each). Tramadol 500 mg was the lowest dose associated with seizure, tachycardia, hypertension or agitation while 800 mg was the lowest dose associated with coma and respiratory depression. Urine drug screens performed on 19 patients were negative for opiates. All symptomatic cases exhibited effects within 4 h of ingestion. Mean hospital stay was 15.2 h (range 2-96 h, SD 15.8). Nineteen patients were admitted to an intensive care unit with a mean stay of 25 h (SD 20).. Much of the toxicity in tramadol overdose appears to be attributable to the monoamine uptake inhibition rather than its opioid effects. Agitation, tachycardia, confusion and hypertension suggest a possible mild serotonin syndrome. No arrhythmias beyond tachycardia were seen.. This study suggests significant neurologic toxicity from tramadol overdose. Serious cardiovascular toxicity was not seen.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Child; Child, Preschool; Drug Overdose; Female; Humans; Infant; Male; Middle Aged; Naloxone; Narcotic Antagonists; Poison Control Centers; Prospective Studies; Seizures; Tramadol

Homophtalazines show specific binding sites in the nigrostriatal system and to find their target of action the interactions between these derivatives, nerisopam and girisopam, and chlorpromazine, chlordiazepoxide and morphine were assessed. The compounds did not influence the chlorpromazine induced decrease in motility and catalepsy, nor did they alter the antiaggressive and anticonvulsive action of chlordiazepoxide. However, nerisopam and girisopam augmented the agonist potency of morphine to induce catalepsy or analgesia; they also altered the opioid antagonist potency of naloxone. The naloxone-induced decrease in sucrose consumption in drinking water was augmented by nerisopam and girisopam. It is suggested that a possible target of action of homophtalazines is the opioid signal transduction.

Topics: Aggression; Analgesics, Opioid; Animals; Anti-Anxiety Agents; Anticonvulsants; Benzodiazepines; Catalepsy; Drinking; Electroshock; Male; Mice; Mice, Inbred Strains; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Rats; Rats, Wistar; Reaction Time; Seizures

The potentiation of the toxic and lethal effects of cocaine by the selective delta-opioid receptor antagonist naltrindole was explored in unrestrained, unanesthetized rats that received a continuous intravenous infusion of cocaine until death. The lethal dose of cocaine was lowered dose dependently in animals administered naltrindole intracisternally (3.0-30 microg), but not intravenously (30-300 microg). There was also a decrease in the lethal dose of cocaine following an injection of the nonselective opioid antagonist naltrexone, but not naloxone. However, the seizure-producing dose of cocaine was decreased dose dependently in rats that received naltrindole, regardless of the route of administration, naloxone, or naltrexone. In contrast, the effect of cocaine on heart rate was altered only by centrally administered naltrindole or intravenous naltrexone, with a dose of 30 microg naltrindole and 10 mg/kg naltrexone abolishing the bradycardic effect of cocaine. Despite this, neither naltrindole nor naltrexone changed the hypertensive effect of cocaine. Higher doses of naltrindole (100 microg i.c.) produced significant increases in heart rate and mean arterial pressure and were not tested in combination with cocaine. Because the lethal dose of cocaine was reduced only when naltrindole was administered intracisternally, the potentiation of the lethal effects of cocaine by naltrindole is through a central mechanism of action that may involve changes in cardiovascular function.

Topics: Animals; Blood Pressure; Central Nervous System; Cisterna Magna; Cocaine; Drug Synergism; Heart Rate; Infusions, Intravenous; Injections; Male; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Seizures

The effects of injections of naloxone, a universal opioid receptor antagonist, into the medial septal nucleus on hippocampal acetylcholine (ACh) release and behavior were investigated in freely moving rats by means of the microdialysis method. The injection of naloxone (2, 10 and 20 micrograms) produced a marked increase in hippocampal ACh release in a dose-dependent manner. These effects of naloxone were reversed by the post-injection of [D-Ala2, N-Me-Phe4, Gly-ol]-enkephalin (DAGO; 10 micrograms), an opioid mu receptor agonist. Furthermore, basal release of hippocampal ACh was significantly reduced by the injection of DAGO alone. It was also found that rats given an injection of naloxone showed an increase in motor activity and occasionally exhibited behavioral seizures. These effects of naloxone were also reversed by the post-injection of DAGO. The present results suggest that endogenous opioids ionically inhibit the activity of septo-hippocampal cholinergic neurons via mediation of mu opioid receptors in the medial septal nucleus. They also suggest that endogenous opioids modulate the incidence of seizures, at least in part, through opioid mu receptors in the medial septal nucleus.

Topics: Acetylcholine; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Hippocampus; Male; Naloxone; Rats; Rats, Wistar; Seizures; Septal Nuclei; Time Factors

The opioid antagonist naloxone is widely used in the emergency treatment of nontraumatic coma. Although it is uncommon for serious side effects to result from administration of opiate antagonists, we report that naloxone can have epileptogenic effects in the context of encephalitis. In an experimental model of viral encephalitis, rats infected with Borna disease virus developed myoclonic, generalized clonic, or atonic seizures; behavior arrest; and staring spells when treated with naloxone. These findings suggest a novel neuropharmacologic link, through opioid peptide systems, between epilepsy and encephalitis and disclose a potential contraindication to use of opioid antagonists in nontraumatic coma.

Topics: Animals; Borna Disease; Contraindications; Dyskinesia, Drug-Induced; Encephalitis, Viral; Male; Naloxone; Rats; Rats, Inbred Lew; Seizures

1. The effects of orally administered aqueous lyophilized extract of the leaves of Rhazya stricta (2, 4 & 8 g/kg) on aspects of nervous system function were investigated in mice. 2. In three antinociceptive tests (hot plate, abdominal constriction, and warm water tail flick tests), the extract exhibited dose-dependent and significant antinociceptive activity. Naloxone was ineffective in antagonizing the analgesic effect of Rhazya stricta on tail-flick and abdominal constriction tests, possibly indicating that this effect occurs via non-opiate pathways. 3.Pretreatment of mice with the xenobiotic metabolizing enzymes inhibitor cimetidine (50 mg/kg) did not significantly alter the antinociceptive action of the extract, indicating that the effect is probably due to the parent compound(s) present in the extract and not to metabolites thereof. 4. Rhazya stricta produce dose-dependent sedation, decreased motor activity, and impaired motor control. Time spent on a rotarod treadmill was significantly decreased after treatment with the extract. 5. Rhazya stricta extract (8 g/kg) produced a degree of sedation comparable to that produced by diazepam (5-10 mg/kg), and also significantly increased the reaction time of the tail-flick test, an action which was not produced by diazepam. 6. Administration of R. stricta extract potentiated pentobarbitone sleeping time in a dose dependent manner. The extract did not significantly antagonize picrotoxin induced convulsions. The extract (4 and 8 g/kg) significantly decreased the rectal temperature of normothermic and hyperthermic mice. 7. Pretreatment with R. stricta extract (8 g/kg) completely prevented the occurrence of aggressive behaviour in male mice. 8. It is concluded that the crude extract of R. stricta has central nervous system depressant properties.

Topics: Abdomen; Analgesia; Animals; Behavior, Animal; Body Temperature; Central Nervous System; Cimetidine; Diazepam; Dose-Response Relationship, Drug; Drug Interactions; Hypnotics and Sedatives; Male; Medicine, Arabic; Mice; Motor Activity; Naloxone; Pentobarbital; Picrotoxin; Plant Extracts; Plant Leaves; Plants, Medicinal; Seizures; Sleep; Tail

Morphine, fentanyl and pethidine exhibited a biphasic dose response relationship with respect to their effects on seizure thresholds to bicuculline, pentylenetetrazole, N-methyl-DL-aspartate (NMDLA) and kainic acid in mice. The usual pattern was for low doses to be anticonvulsant and higher doses to be proconvulsant. However this pattern was reversed for fentanyl and pethidine when NMDLA was used to induce seizures. The low dose effects of all three opioid drugs was sensitive to 1 mg kg-1 naloxone in all seizure models. The responses to high doses of pethidine were unaffected or enhanced by this dose of naloxone. Naloxone reversed the effects of the higher doses of morphine and fentanyl in all models except bicuculline induced seizures.

Topics: Analgesics, Opioid; Animals; Anticonvulsants; Bicuculline; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Kainic Acid; Male; Mice; N-Methylaspartate; Naloxone; Pentylenetetrazole; Seizures

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.

Topics: Animals; Avoidance Learning; Dose-Response Relationship, Drug; Kindling, Neurologic; Learning Disabilities; Male; Naloxone; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Sodium Chloride

The effects of some beta-endorphin fragments with neuroleptic-like properties, i.e., tau-endorphin, des-tyr1-tau-endorphin (DT tau E), desenkephalin-tau-endorphin (DE tau E), in comparison with the dopaminergic antagonist haloperidol,- were studied on the EEG and behavioral alterations induced by beta-endorphin in the rabbit. beta-Endorphin administered i.c.v. (5-30 nmol) induced EEG nonconvulsive limbic seizures as well as EEG background and behavioral alterations which were antagonized by naloxone administered i.v. (1-2 mg/kg). Haloperidol, tau-endorphin, DT tau E and DE tau E were unable to prevent beta-endorphin-induced alterations when injected in a single dose i.v. (25-50 micrograms/kg), 15 min before beta-endorphin. Subchronic i.v. administration of DT tau E or DE tau E (25 micrograms/kg/day) for 4 consecutive days prevented completely EEG limbic seizures as well as EEG background and behavioral alterations induced by i.c.v. beta-endorphin injected 15 min after the fourth dose; however, haloperidol (30 micrograms/kg/day) administered with the same schedule as DT tau E or DE tau E was able to prevent only EEG epileptiform and EEG background alterations induced by beta-endorphin. tau-Endorphin administered i.v. for 4 consecutive days (25 micrograms/kg/day) did not consistently influence any of the beta-endorphin effects. Our results show that DT tau E and DE tau E, which are devoid of opioid activity, exert a strong antagonism on ictal seizures as well as on other EEG alterations and behavioral alterations induced by beta-endorphin, and suggest that the antagonism shown by these drugs and by haloperidol on the EEG effects induced by beta-endorphin are exerted at least in part through an indirect action, i.e., an interaction with the dopaminergic system.

Topics: Animals; Behavior, Animal; beta-Endorphin; Electroencephalography; Endorphins; Haloperidol; Injections, Intraventricular; Male; Naloxone; Peptide Fragments; Rabbits; Seizures

This study investigates the possible involvement of opioid receptors in the action of a variety of anticonvulsant agents. The opioid antagonist naloxone (0.3, 1 mg/kg IP) and the selective mu-opioid antagonist cyprodime (3 mg/kg IP) significantly inhibited the increase in electroshock seizure threshold induced by phenytoin (3 mg/kg IP) in mice. The anticonvulsant effects of ethanol (1 g/kg IP) were also significantly antagonised by naloxone (1 mg/kg IP) but not by a 0.3 mg/kg IP dose or by cyprodime (3 mg/kg IP). The results with naloxone were confirmed using higher doses of phenytoin (10 mg/kg IP) and ethanol (1.5 g/kg IP). In contrast to the above findings, naloxone (0.3, 1 mg/kg IP) had no effect on the increase in seizure threshold induced by sodium valproate (200 mg/kg IP) or dizocilpine (MK801, 0.5 mg/kg IP) and paradoxically potentiated the increase in seizure threshold produced by phenobarbitone (15 mg/kg IP); carbamazepine (10 mg/kg IP) and the benzodiazepine agonist loprazolam (1 mg/kg IP), clearly differentiating these compounds from phenytoin and ethanol. These findings suggest that the anticonvulsant effects of phenytoin and ethanol (as assessed by their ability to prevent tonic hindlimb extension in the mouse electroshock model) may be mediated, at least in part, by the release of endogenous opioids and subsequent activation of opioid receptors (mu, in the case of phenytoin, but non-mu, in the case of ethanol) although direct activity at opioid receptors cannot be precluded.

Topics: Animals; Anticonvulsants; Dose-Response Relationship, Drug; Electroshock; Male; Mice; Mice, Inbred Strains; Morphinans; Naloxone; Narcotic Antagonists; Phenytoin; Receptors, Opioid; Receptors, Opioid, mu; Seizures

After the intracisternal injection of three protease inhibitors which prevent the degradation of methionine enkephalin (amastatin, Des-Pro2-bradykinin, and phosphoramidon) and a mixture of these protease inhibitors, we investigated the effect on convulsive seizures in the seizure-susceptible El mouse. We also measured the cerebral methionine enkephalin content by high-performance liquid chromatography coupled with radioimmunoassay. Protease inhibitors significantly decreased both the incidence of seizures and the seizure score in El mice in a dose-dependent manner. This anticonvulsant effect was reversed by naloxone (2 mg/kg, sc). The cerebral methionine enkephalin content increased significantly after the administration of protease inhibitors in comparison with saline injection. These findings suggest that it was not protease inhibitors but instead increase of endogenous methionine enkephalin that reduced the incidence of seizures and the seizure score in El mice. Together with our previous data, the present findings support our hypothesis that a deficit in anticonvulsant endogenous methionine enkephalin is involved in the pathogenesis of seizures in the El mouse.

Topics: Animals; Anti-Bacterial Agents; Bradykinin; Brain; Chromatography, High Pressure Liquid; Enkephalin, Methionine; Glycopeptides; Mice; Mice, Mutant Strains; Naloxone; Peptides; Protease Inhibitors; Radioimmunoassay; Seizures

The role of opiate mechanisms in the development of tolerance and altered susceptibility to seizures after repeated injections of picrotoxin was investigated. Independent groups of rats were pretreated with naloxone (0.3, 1.0, 3.0, and 10.0 mg/kg) or the saline vehicle and then tested for seizures induced by picrotoxin. The procedure was performed on 3 days at 1-week intervals, for a total of 3 testing days. Latencies to different types of seizures, the duration of postseizure immobility, and the number of focal seizure episodes were scored. In the vehicle-treated group, repeated picrotoxin injections led to an increased susceptibility to myoclonic and focal seizures and to decreased duration of postseizure immobility. Naloxone pretreatment significantly decreased the duration of the postseizure akinetic periods in the 1.0- and 10.0-mg/kg groups across all days, suggesting that endogenous opiates are involved in postseizure immobility and that there are interactions between opiate and picrotoxin mechanisms in some seizure-related behaviors. Naloxone did not alter the development of tolerance or sensitivity, indicating that naloxone-insensitive opiate mechanisms or nonopiate mechanisms may be involved in these processes.

Topics: Animals; Behavior, Animal; Drug Tolerance; Epilepsies, Myoclonic; Epilepsies, Partial; Kindling, Neurologic; Male; Motor Activity; Naloxone; Picrotoxin; Rats; Seizures

This study describes the chemical synthesis and receptor binding characteristics of various affinity ligands and related ligands for brain muscarinic and nicotinic cholinergic receptors, including the 4-bromoacetamidobenzoic acid esters of dimethylaminoethanol (DMBAB) and choline (BABC) and 4-iodoacetamidobenzoylcholine (IABC). The reversible binding of [3H]3-quinuclidinylbenzilate ([3H]QNB) to calf brain membranes was inhibited in a concentration-dependent and saturable manner by DMBAB, BABC, and IABC with Ki values of 8 x 10(-7), 3 x 10(-7) and 8 x 10(-7) M, respectively; the Ki values for inhibition of reversible binding of the nicotinic ligand, [3H]methylcarbamylcholine ([3H]-MCC), were 1 x 10(-6), 6 x 10(-8), and 1 x 10(-6) M, respectively. The Ki values for irreversible inhibition of [3H]QNB binding were 8 x 10(-7), 1 x 10(-7), and 2 x 10(-7) M for DMBAB, BABC, and IABC, respectively, and for [3H]MCC binding, 8 x 10(-5), 1 x 10(-5), and 2 x 10(-5) M, respectively. Although DMBAB was found to inhibit the QNB-induced hyperactivity in mice, it did not antagonize the toxic or other pharmacologic effects of oxotremorine. Structure-activity studies with various non-affinity analogues of the 4-aminobenzoate ester of dimethylaminoethanol and choline revealed that removal of the NH2 moiety from the phenyl group increased affinity for the muscarinic but not the nicotinic cholinergic site, and quaternization of the ester side chain greatly increased affinity for the muscarinic site. Dimethylation of NH2 in 4-aminobenzoylcholine decreased the affinity for both cholinergic sites. Replacement of NH2 by NO2 increased affinity for the muscarinic but not the nicotinic site, whereas quaternization of the 4-nitrobenzoyl ester markedly increased affinity for the nicotinic site while diminishing affinity for the muscarinic site. The findings indicate that DMBAB and its analogues are useful affinity ligands for examining the biochemical and functional characteristics of brain cholinergic receptors, particularly the muscarinic which has an affinity near the nanomolar concentration range.

Topics: Affinity Labels; Animals; Brain; Carbachol; Choline; Kinetics; Ligands; Mice; Naloxone; Nicotine; Oxotremorine; Procaine; Quinuclidinyl Benzilate; Receptors, Muscarinic; Receptors, Nicotinic; Seizures; Tritium

Past research has demonstrated brain opioid and GABA release in response to ejaculation. In the present study we evaluated the potential role of these neurotransmitters in the postictal behavioral depression (PBD), after-discharge (AD) duration, and seizure intensity in rats kindled in the medial preoptic area (MPOA) and amygdala (AMG). The PBD, the AD duration and the seizure intensity were measured after a standard kindling stimulus and after a standard kindling stimulus applied 2 min after ejaculation. The PBD was significantly increased when the animals were stimulated 2 min after ejaculation. This increase was found in MPOA- but not in AMG-kindled rats. Ejaculation had no effect on AD duration or seizure intensity. Naloxone administration before the initiation of sexual behavior completely blocked the increase in PBD in MPOA-kindled rats. It is suggested, by indirect evidence, that opioid release during sexual behavior is added to the release associated with kindled seizures, increasing the duration of the PBD. Since sexual behavior lacked effect on AD duration or seizure intensity, no evidence could be found suggesting that functionally relevant amounts of GABA are released during this behavior.

Topics: Amygdala; Animals; Behavior, Animal; Ejaculation; Electric Stimulation; Electrophysiology; Endorphins; Kindling, Neurologic; Male; Naloxone; Preoptic Area; Rats; Rats, Wistar; Seizures; Sexual Behavior, Animal

Opioid agonists were used to investigate the modulation of seizures in the seizure-susceptible El mouse. Morphine and D-Ala2-D-Leu5-enkephalin (DADLE) were injected subcutaneously or intracisternally as prototypic agonists for mu and delta opioid receptors. Systemic or intracisternal injection of both morphine and DADLE decreased the incidence of seizures and the seizure score in El mice in a dose-dependent manner. The anticonvulsant effects of morphine and DADLE were reversed by naloxone (2 mg/kg, s.c.). This implies that opioid agonists have anticonvulsant properties which are mediated by mu and delta opioid receptors. In conclusion, a deficit in endogenous opioid peptides, which act as anticonvulsants may play a significant role in the etiology or pathophysiology of seizures in the El mouse.

Topics: Animals; Anticonvulsants; Enkephalin, Leucine-2-Alanine; Mice; Mice, Mutant Strains; Morphine; Naloxone; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Seizures

The effect of morphine and naloxone on acute cocaine toxicity was studied. Male Sprague-Dawley rats were pretreated intraperitoneally (ip) with saline, morphine sulfate 25 mg/kg, or naloxone 1.0 mg/kg 15 minutes prior to challenge by cocaine. After pretreatment, each group was challenged with one of three doses of cocaine (35, 50, or 75 mg/kg ip). Each of the nine drug combinations was tested on at least 10 animals. Animals were observed for behavior, seizures, and death. The animals pretreated with saline and challenged with cocaine (35, 50, or 75 mg/kg) had seizure incidences of 0%, 40%, and 100%, respectively, after increasing doses. Pretreatment with morphine resulted in cocaine-induced seizures of 20%, 80% and 100%, respectively (p less than or equal to 0.05 with cocaine 35 and 50 mg/kg). Time to seizures in these groups did not differ significantly compared to the saline groups. Pretreatment with naloxone resulted in cocaine-induced seizures of 0%, 50%, and 60% (p less than or equal to 0.05 at the 75 mg/kg dose). The incidence of death was significantly increased by pretreatment with morphine in animals that received cocaine 50 or 75 mg/kg. The time to death was not significantly different compared to saline controls. The death rate in naloxone pretreated animals was not significantly different from the saline groups. In additional studies, high-dose naloxone pretreatment (10 mg/kg) also failed to provide protection from acute cocaine toxicity. In conclusion, cocaine toxicity is potentiated by morphine and does not appear to be altered by naloxone.

Topics: Animals; Cocaine; Death; Dose-Response Relationship, Drug; Drug Administration Schedule; Male; Morphine; Naloxone; Rats; Rats, Inbred Strains; Seizures

This study describes the synthesis, receptor binding characteristics, and some behavioral effects of p-bromoacetamidoprocaine (BAP), a new affinity ligand for brain muscarinic and nicotinic cholinergic receptors. The reversible binding of [3H]QNB to rat brain membranes was inhibited in a concentration dependent and saturable manner by both procaine and BAP, with Ki values of 4 x 10(-6) and 3 x 10(-7) M, respectively, and complete inhibition at 1 x 10(-5) M. Both procaine and BAP, although at much concentrations, inhibited the binding of [3H]methylcarbamylcholine in a concentration dependent manner, with Ki values of 5 x 10(-5) and 1 x 10(-5) M, respectively, and complete inhibition for both at 1 x 10(-3) M. Plots of the % irreversible inhibition of [3H]QNB, [3H]nicotine, and [3H]MCC vs [BAP] yielded Ki values of 7 x 10(-8), 1 x 10(-4), and 6 x 10(-5) M, respectively. In behavioral studies BAP was able to antagonize the QNB-induced hyperactivity in mice; however, BAP did not appear to alter nicotine-induced seizure activity or other behavioral effects in mice. A plot of the time course of inhibition by BAP for [3H]QNB binding revealed that the inhibition was almost complete within 10 min exposure at 37 degrees. The findings indicate that BAP is a useful affinity ligand for examining the biochemical and functional characteristics of brain cholinergic receptors, particularly the muscarinic which has an affinity near the nM concentration range.

Topics: Animals; Behavior, Animal; Brain; Carbachol; Chloromercuribenzoates; Hyperkinesis; Ligands; Mercaptoethanol; Molecular Structure; Naloxone; Nicotine; p-Chloromercuribenzoic Acid; Procaine; Quinuclidinyl Benzilate; Radioligand Assay; Receptors, Muscarinic; Receptors, Nicotinic; Seizures

Intracerebroventricular (ICV) administration of kappa-agonists (PD 117302, U-50488H and U-69593) induced convulsions in a dose-related manner in mice. The dose at which 50% of animals convulsed (CD50) was in nmol ranges for all opioids. Among the opioids used, PD 117302 was the most potent convulsant. ICV administration of either vehicle alone or U-53445E, a non-kappa-opioid (+) enantiomer of U-50488H did not induce convulsions. The convulsive response of kappa-agonists was differentially susceptible for antagonism by naloxone and/or MR 2266. Collectively, these findings support the view that convulsions induced by kappa-agonists in mice involve stereospecific opioid receptor mechanisms. Furthermore, the convulsant effect of kappa-agonists could not be modified by pretreatment with MK-801, ketamine, muscimol or baclofen. It is concluded that kappa-opioid but not NMDA or GABA receptor mechanisms are involved in convulsions induced by kappa-agonists. These results are the first experimental evidence implicating stereospecific kappa-receptor mechanisms in opioid-induced convulsions in mice.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Baclofen; Benzeneacetamides; Benzomorphans; Cerebral Ventricles; Convulsants; Dizocilpine Maleate; Injections, Intraventricular; Ketamine; Mice; Mice, Inbred Strains; Muscimol; Naloxone; Narcotic Antagonists; Narcotics; Pyrroles; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Seizures; Stereoisomerism; Thiophenes

Electroconvulsive shock-induced seizures elevate seizure thresholds in humans and interfere with kindling in animals; opioids may mediate the anticonvulsant mechanism. In a potential model of acute electroconvulsive shock in hippocampal slices, a high-intensity tetanus via the mossy fibers substantially delayed subsequent in vitro kindling through the Schaffer collaterals. Naloxone blocked this effect, implicating the opioid system in the antiepileptogenic properties of this model.

Topics: Animals; Electroshock; Hippocampus; In Vitro Techniques; Kindling, Neurologic; Naloxone; Neurotransmitter Agents; Rats; Seizures

We have investigated in mice the effects of several drugs which may be administered as part of an anaesthetic technique on the convulsive threshold to laudanosine and to strychnine, which is reported to have a similar mechanism of action. I.v. administered propofol, thiopentone and midazolam increased the dose of convulsant necessary to produce seizure when administered 2 min before the convulsive stimulus. In contrast, methohexitone and etomidate exhibited a proconvulsant effect, although with the latter this was significant only in laudanosine-treated mice. Pethidine was proconvulsant in both laudanosine- and strychnine-treated mice, but morphine was proconvulsant only in strychnine-treated mice. The effects of morphine, but not pethidine, were antagonized by naloxone 1 mg kg-1. Laudanosine, but not strychnine caused arousal from anaesthesia in subconvulsive doses. This and other evidence suggests that the mechanism of the CNS excitation produced by strychnine and laudanosine are not the same.

Topics: Analgesics; Anesthetics; Animals; Arousal; Brain; Drug Interactions; Female; Isoquinolines; Mice; Morphine; Naloxone; Seizures; Strychnine

Topics: Animals; Arousal; Brain Mapping; Diazepam; Electroencephalography; Hippocampus; Kindling, Neurologic; Male; Naloxone; Phenytoin; Rats; Rats, Inbred Strains; Restraint, Physical; Seizures; Stress, Psychological

The effects of the opiate antagonist, naloxone, on seizure tendencies of the black or nonagouti line of Mongolian gerbils (Meriones unguiculatus) carrying the a/a coat color allele was investigated. The animals were tested under the following conditions: mock infection; 0.9% NaCl injection; and naloxone at doses of 1, 2, 5, and 10 mg/kg body weight. The results indicated that when naloxone was at doses of 2 mg/kg body weight and higher, there was an increase in the animals' seizure latencies relative to that manifested under the basal condition.

Topics: Animals; beta-Endorphin; Brain; Dose-Response Relationship, Drug; Electroencephalography; Gerbillinae; Naloxone; Reaction Time; Seizures

The effects of microinjection of naloxone, an opiate receptor antagonist, into the medial preoptic area (MPO) and diagonal band of Broca (DBB) on luteinizing hormone (LH) and prolactin (PRL) secretion were examined in the intact male rat and female rat in diestrus 1. In both the male and female rats, the injection of 50 micrograms naloxone at 1300 h produced an acute, two- to three-fold increase in serum LH, attaining the peak at 20 min. The PRL concentration in the female 20 min-2 h after the injection was significantly lower than in the saline-injected rat. In the male rat, naloxone caused a decrease in the PRL concentration in the late afternoon when a small rise occurred in the saline-injected rat, although it caused no immediate changes. In addition to these hypophysiotropic effects, naloxone injected in the MPO and DBB unexpectedly had seizurogenic actions. More than 40% of the animals of both sexes given an injection of naloxone had behavioral seizures, which began after about 20 min and were repeated intermittently at 15-20 min intervals through the sampling period of 6 h. In the LH and PRL response to naloxone, there was no significant difference between animals with and without seizure response in both sexes. The results suggest that in the preoptic opioid system there is no difference according to sex in the control of LH, and only a small one, if any, in the control of PRL. Further, on the basis of previous reports, there is a GABAergic system in the preoptic region, that is antagonized by naloxone and causes the activation of cortical neuronal activity.

Topics: Animals; Diestrus; Electroencephalography; Female; Frontal Lobe; Luteinizing Hormone; Male; Naloxone; Preoptic Area; Prolactin; Radioimmunoassay; Rats; Rats, Inbred Strains; Seizures; Sex Characteristics; Testis

The influence of two stressogenic conditions, restraint at 4 degrees C for 30 min (cold-restraint stress; CRS) or swimming at 20 degrees C for 3 min (swim stress; SS), on nociception and on convulsions triggered by different agents was assessed in mice. In saline-pretreated mice CRS and SS caused analgesia (hot-plate test, 56 degrees C), delayed the onset of convulsions induced by pentylenetetrazol (PTZ, 100 mg/kg, IP) and aggravated convulsions elicited by maximal transcorneal electroshock (150 mA pulses at 60 Hz for 0.2 s). Pretreatment with naloxone (10 mg/kg, SC, 30 min prior to testing), which did not affect the responsiveness of nonstressed mice to the hot plate or to the convulsant treatments, attenuated the development of analgesia following CRS, but not SS, and further prolonged the latency to onset of PTZ-induced convulsions in both stressed groups. Thus the extent to which CRS and SS can each delay the onset of PTZ-triggered convulsion appears to be limited by activation of a proconvulsant opioid system. In contrast, naloxone pretreatment did not modify the effects of CRS or SS on the severity of electroshock-induced seizures. In conclusion, CRS and SS can each, simultaneously, exert anticonvulsant and proconvulsant influences on responsiveness to PTZ and electroshock, respectively. Also, both forms of stress can activate an opioid system modulating the onset of PTZ-induced seizures, which is distinct from that controlling nociception. These findings, together with those of other stress, convulsions and opioid systems, which depends on the characteristics of the stressogenic condition, species, convulsant agent and parameter considered.

Topics: Analgesia; Animals; Cold Temperature; Electroshock; Male; Mice; Naloxone; Pain Measurement; Pentylenetetrazole; Restraint, Physical; Seizures; Stress, Psychological; Swimming

The disparity between the seizure sensitivity of the dorsal and ventral hippocampus to opioid peptides was studied by an in vitro electrophysiological method. Slices taken from the ventral (temporal) and dorsal (septal) regions of rat hippocampi were perfused in artificial cerebrospinal fluid bubbled continuously with 95% O2-5% CO2 at 34 degrees C. A stimulating electrode was placed in the stratum radiatum of CA3 region and electrical activity was recorded from the pyramidal cell body layer of the CA3b region. Paired dorsal and ventral hippocampal slices were perfused with [N-Me-Phe3-D-Pro4]morphiceptin (PL017), a specific mu opioid receptor agonist. Application of 0.05 microM PL017 produced triggered and spontaneous bursting in 20% of ventral hippocampal slices, but no such effect was observed in dorsal hippocampal slices. At 0.5 microM PL017, 80% of ventral hippocampal slices developed spontaneous bursting, whereas only 10% of dorsal hippocampal slices had spontaneous bursting. Slices from the ventral hippocampus consistently produced greater degrees of bursting at lower doses relative to the dorsal hippocampus. The addition of 0.1 microM naloxone before or after PL017 inhibited the triggered response but could not block the spontaneous bursting. Perfusion of ACSF for 1 hr also eliminated the triggered response but could only reduce the frequency of the spontaneous bursting. These results suggest that the ventral hippocampus has a higher susceptibility to PL017-induced epileptiform bursting, and this effect is mediated, at least in part, through mu opioid receptors.

Topics: Animals; Electrophysiology; Endorphins; Hippocampus; In Vitro Techniques; Male; Naloxone; Rats; Rats, Inbred F344; Receptors, Opioid; Seizures

Administration of morphine into the spinal intrathecal (i.t.) space produced dose-dependent analgesia in the mouse. At higher doses i.t. morphine induced seizures of the hindlimbs. Mice treated chronically with morphine (75 mg pellet, s.c.) for 72 h were tolerant to the analgesic effects of i.t. morphine, but not to the proconvulsant action. Spinal morphine analgesia was attenuated by naloxone, whereas i.t. morphine-induced seizures were not. These results indicate that spinal opioid receptors mediate analgesia but not seizures following i.t. morphine treatment in the mouse.

Topics: Analgesia; Animals; Dose-Response Relationship, Drug; Drug Tolerance; Injections, Spinal; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Seizures; Spinal Cord

To evaluate the safety and possible efficacy of high-dose naloxone for the treatment of acute cerebral ischemia, 38 patients received a loading dose of 160 mg/m2 over 15 minutes followed by a 24-hour infusion at the rate of 80 mg/m2/hr. Nausea and/or vomiting were common side effects. Naloxone was discontinued in seven patients (because of hypotension in one, bradycardia and hypotension in two, myoclonus in one, focal seizures in two, and hypertension in one); all seven patients responded to treatment and no permanent sequelae to naloxone were noted. Twelve of the 38 patients showed early neurologic improvement (by completion of the naloxone loading dose). However, there was no correlation between such a loading dose response and clinical outcome at 3 months. Our experience suggests that naloxone is safe at the dose used, but data for efficacy are inconclusive.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Blood Pressure; Brain Ischemia; Cerebrovascular Disorders; Drug Evaluation; Female; Gastrointestinal Diseases; Humans; Infusions, Intravenous; Male; Middle Aged; Naloxone; Seizures

We performed a retrospective review to investigate the safety of prehospital naloxone administration by paramedics as part of a protocol for all patients presenting with an acutely depressed level of consciousness (LOC). The prevalence of naloxone-induced vomiting, seizures, hypotension, hypertension, and cardiac arrest was sought from the prehospital records of 813 patients treated during a 12-month period. The mean age of the treated patients was 42.4 +/- 9.7 years. The initial dose of naloxone was 0.4 to 0.8 mg, and the mean total dose was 0.9 +/- 0.6 mg. No patients lost a pulse within ten minutes of receiving naloxone. Two patients (0.2%) experienced a significant drop in systolic blood pressure, and one patient (0.1%) demonstrated a significant rise in systolic blood pressure within five minutes of naloxone administration. Vomiting occurred in two patients (0.2%), and one patient (0.1%) suffered a tonic-clonic seizure within five minutes of naloxone administration. Of the 813 patients treated, 60 patients (7.4%: mean age, 32.3 +/- 6.7 years) were judged to have an improved LOC after naloxone, with 27 (3.3%) regaining a normal LOC. We conclude that in the above doses, naloxone is safe as part of prehospital protocols for paramedics treating patients with an acutely depressed LOC. However, the vast majority of patients treated empirically with naloxone in the field demonstrated no benefit.

Topics: Adult; Emergencies; Emergency Medical Services; Female; Heart Arrest; Humans; Hypotension; Male; Middle Aged; Naloxone; Pennsylvania; Retrospective Studies; Safety; Seizures; Unconsciousness; Vomiting

The effects of a selective kappa-agonist, U-50,488H, on systemic kainic acid-induced behavioral and histological changes were studied in rats. U-50,488H inhibited kainic acid-induced wet dog shakes in a naloxone reversible manner; however, U-50,488H did not protect rats against kainic acid-evoked behavioral seizures. As revealed by histological analysis, kainic acid caused edema and severe neuronal damage in several brain regions, notably in CA1 but also in the CA3 fields of both hippocampi. Pretreatment of rats with U-50,488H markedly protected hippocampal neurons, especially those in CA1, against kainic acid-induced neurotoxicity. Naloxone by itself had little effect on kainic acid-induced seizures or hippocampal neuron loss. Naloxone plus U-50,488H resulted in less severe seizures and, consequently, less hippocampal cell loss than after kainic acid alone. These data indicate that U-50,488H can markedly attenuate the neurotoxic and behavioral consequences of systemic kainic acid administration. However, the mechanism of these effects requires further study with more specific opioid antagonists.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Behavior, Animal; Brain; Kainic Acid; Male; Naloxone; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Seizures

Topics: Female; Humans; Infant, Newborn; Naloxone; Neonatal Abstinence Syndrome; Opium; Pregnancy; Seizures; Time Factors

The non-specific opiate antagonist naloxone protects immature rats from hyperthermic seizures which occur when the animals are exposed to an environment of 40 degrees C and 55% humidity. Most of the currently used antiepileptic therapeutic agents can be said to contain either a hydantoin or a moiety stereochemically closely related to one. We have added a hydantoin group to naloxone and created a new combined chemical, naloxyl-6-alpha spirohydantoin. The new compound was ten times as effective as naloxone against hyperthermic seizures in 15-day old rat pups. Unlike naloxone, the new naloxone-hydantoin derivative retained a protective effect 24 hrs after injection.

Topics: Animals; Body Temperature; Environment, Controlled; Fever; Hydantoins; Hyperthermia, Induced; Naloxone; Rats; Rats, Inbred Strains; Seizures; Sodium Chloride

We induced generalized seizures by cortical injection of penicillin in anesthetized, paralyzed cats. After they had developed recurrent ictal-interictal ECoG cycling and fictive tonic-clonic motor convulsions (status epilepticus), we studied the effect of systemically administered neuropharmacological agents on the seizure cycling. Antagonists of adenosine receptors, theophylline and 8-cyclopentyltheophylline, increased the cycle period due to marked prolongation of duration of ictal discharge, often to more than 30 min. Dipyridamole, an inhibitor of adenosine reuptake, lengthened the interictal phase of the seizure with no effect on ictal duration. Antagonists of gamma-aminobutyric acid and opioid peptides had no effect on either ictal or interictal phases nor did the nonspecific neural excitant, doxapram. These findings suggest that a major mechanism of ictal-interictal cycling during status epilepticus is the alternating accumulation during the ictal phase and clearance during the interictal phase of the inhibitory neurochemical, adenosine.

Topics: Adenosine; Animals; Bicuculline; Blood Pressure; Cats; Cerebral Cortex; Dipyridamole; Doxapram; Naloxone; Penicillins; Receptors, Purinergic; Reference Values; Seizures; Theophylline

Topics: Emergencies; Humans; Male; Middle Aged; Naloxone; Seizures

The biochemical and pharmacological properties of an endogenous anticonvulsant substance(s) found in rat cerebrospinal fluid (CSF) following seizures are described. CSF taken from donor rats following a single maximal electroshock (MES) seizure caused significant elevations in seizure thresholds in naive recipient rats when intracerebroventricularly injected 15 min prior to exposure to the volatile convulsant flurothyl. Anticonvulsant activity was antagonized by pre-injection in recipients of high doses of naloxone or the selective delta-opioid receptor antagonist ICI 174,864. The anticonvulsant activity was also lost when the CSF was exposed to heat (90 degrees C) or immobilized trypsin. Although unaffected by the peptidase inhibitors thiorphan and bestatin, the anticonvulsant activity was significantly potentiated by a combination of aprotinin and bacitracin. Ultrafiltration of CSF revealed that the anticonvulsant activity passed through membranes with a 10,000 molecular weight cut-off, but was retained by membranes with a 5000 molecular weight cut-off. CSF removed from rats following MES had significantly increased concentrations of beta-endorphin-like, but not dynorphin A, Leu- or Met-enkephalin-like immunoreactivities relative to CSF from sham-treated rats. However, significant increases in Met-enkephalin-like immunoreactivity were measured following exposure of the CSF to the proteolytic enzymes trypsin and carboxypeptidase B, suggesting the seizure-induced presence of a higher molecular weight form of Met-enkephalin not recognized immunologically prior to enzyme exposure. These data reconfirm the anticonvulsant actions of postseizure CSF, and indicate that these effects require mediation through delta-opioid receptors in the recipient rat. These data additionally argue against these effects being mediated by Met-enkephalin, Leu-enkephalin or dynorphin A in the CSF, and suggest instead that anticonvulsant effects are attributable to a heat- and trypsin-sensitive opioid peptide(s) with a molecular weight approximately in the range of 5000-10,000 Da.

Topics: Animals; Anticonvulsants; Aprotinin; Bacitracin; Endorphins; Male; Molecular Weight; Naloxone; Rats; Rats, Inbred Strains; Receptors, Opioid; Seizures

The effects of mu-agonists (morphine, fentanyl) and kappa-agonists (U-50,488, U-69,593, bremazocine, nalbuphine, tifluadom) on the electroconvulsive threshold were studied in mice. The threshold could be significantly elevated by all drugs tested in a dose range that was in the order of magnitude of the antinociceptive ED50. Mice tolerant to the antielectroshock effect of morphine still reacted to U-69,593. The antagonism of the anticonvulsant effect by the mu-antagonist naloxone and the kappa-antagonist MR 2266 was receptor-specific only with fentanyl and U-50,488. The other opioid agonists were either antagonized by both drugs (morphine, U-69,593, bremazocine, nalbuphine) or even by the opposite antagonist (tifluadom). A synergistic effect of mu- and kappa-stimulation is assumed for the mediation of the antielectroshock effect of opioid drugs, but drugs with high affinity and intrinsic activity at one receptor type (fentanyl, U-50,488) are obviously able to bring about their antielectroshock effect through the one respective opioid binding site.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzeneacetamides; Benzodiazepines; Benzomorphans; Electroshock; Fentanyl; Male; Mice; Morphinans; Morphine; Nalbuphine; Naloxone; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Seizures

This paper describes experiments designed to evaluate whether the narcotic antagonist naloxone significantly interferes with seizures induced by tetrahydroisoquinolines (TIQs). In these experiments we found that naloxone significantly reduced seizure scores induced by intra-cranially infusing mice with 50 micrograms of the dopamine-derived tetrahydroisoquinoline (TIQ) alkaloid, 6,7-dihydroxy TIQ. These findings support an opioid involvement in the actions of TIQs and may lead to further understanding of opioid-mediated novel excitatory receptors.

Topics: Alcoholic Intoxication; Animals; Behavior, Animal; Convulsants; Ethanol; Isoquinolines; Naloxone; Receptors, Opioid; Seizures

The effects of the non-specific opiate antagonist L-naloxone and the inactive isomer D-naloxone, as well as the specific mu receptor antagonist beta-funaltrexamine, have been examined on hyperthermia-induced seizures in unrestrained 15 days old rats. Saline-injected animals exposed to an ambient temperature of 40 degrees C showed a gradual increase in body temperature reaching a maximum of 42 +/- 0.1 degrees C at 50 min exposure. At this time all the pups had seizures and died. Similar results were obtained when the animals were pretreated with different doses of D-naloxone and beta-funaltrexamine. Rats pretreated with L-naloxone also showed an increase in rectal temperature; but the temperature was lower than in saline-injected animals. Only high doses of L-naloxone prevented seizures and deaths. These data indicate that endogenous opioid peptides may play a role in seizures induced by hyperthermia and that receptors other than mu receptors could be involved in hyperthermia-induced seizures.

Topics: Animals; Body Temperature; Hyperthermia, Induced; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Seizures; Stereoisomerism

Interictal changes in locomotor and shock-response behaviors were examined in rats that were kindled unilaterally or bilaterally in the amygdala. 2-Deoxyglucose and naloxone were used to test whether alterations in cerebral glucose metabolism or opioid functioning, respectively, correlated with changes in these behaviors. Bilaterally kindled rats, at 14 to 28 days after their last seizure, displayed increased locomotion (square crossing) in an open field compared with unilaterally kindled or control rats. Bilaterally kindled rats also showed elevated thresholds for the elicitation of a multiple squeak response to tail shocks. Single squeak or tail withdrawal responses to tail shock were not affected by bilateral kindling. Likewise, unilaterally kindled rats did not differ from controls on any of the behavioral measures. Naloxone (10 mg/kg, i.p.) reversed the increase in locomotion and elevation of multiple squeak thresholds in the bilaterally kindled rats. By itself, naloxone did not influence any of the behaviors. Finally, cerebral glucose metabolism was decreased, globally, in the forebrain of the bilaterally kindled rats, and naloxone normalized this change. Cerebral metabolism was not altered in unilaterally kindled rats compared with controls. Thus, changes in cerebral metabolism and opioid functioning may be involved in the mediation of interictal changes in locomotor and emotional behavior in rats.

Topics: Amygdala; Animals; Behavior, Animal; Brain; Deoxyglucose; Electroshock; Endorphins; Kindling, Neurologic; Male; Motor Activity; Naloxone; Rats; Rats, Inbred Strains; Seizures; Tail

The sensitivity to intracerebroventricular morphine-induced convulsions was determined in members of the severe seizure (GEPR-9) and moderate seizure (GEPR-3) colonies of genetically epilepsy-prone rats as well as in non-epileptic control rats. GEPR-9s were more sensitive to morphine-induced wet-dog shakes, rearing with bilateral forelimb clonus and generalized clonus than controls of GEPR-3s. GEPR-3s were less sensitive to morphine-induced wet-dog shakes and rearing with bilateral forelimb clonus than controls. Both high and extremely low doses of morphine in GEPR-9s elicited tonic extensor convulsions resembling the characteristic sound-induced convulsion of GEPR-9s. The results suggest that opiotergic systems may contribute to the pathophysiology of the seizure-prone condition in GEPR-9s. Further, differences in responsiveness of opiotergic systems in GEPR-3s and GEPR-9s may partially account for differences in seizure severity in the characteristic sound-induced seizures of these two types of GEPRs.

Topics: Animals; Epilepsy; Female; Injections, Intraventricular; Male; Morphine; Naloxone; Rats; Seizures

Although the presence of several types of opiate receptors and ligands has been demonstrated within the hippocampus, little is known about the circumstances in which endogenous opiates may be released. Previous studies have suggested that opiates may be involved in producing seizure activity within the hippocampus, or alternatively, that they may be released by seizure activity within the limbic system to prolong the period of postictal depression and thereby prevent the recurrence of seizures during this period. In this experiment we examined the effect of opiate receptor blockade produced by 20 mg/kg ip naloxone on the duration of afterdischarge produced by high-frequency hippocampal stimulation and on inhibition of subsequent seizure activity in male Sprague-Dawley rats. Contrary to the stated hypotheses, naloxone had no effect on either measure.

Topics: Animals; Hippocampus; Male; Naloxone; Rats; Rats, Inbred Strains; Seizures; Synaptic Transmission

We have tested whether the opioid antagonists naloxone (2 mg/kg), naltrexone (2 mg/kg) and diprenorphine (0.2 mg/kg), and the agonist morphine (4-8 mg/kg) given subcutaneously (10 min before ethanol for 7 days) modify the ethanol withdrawal syndrome (audiogenic seizures) following chronic ethanol intoxication in rats. We found that naloxone, naltrexone and diprenorphine modified the ethanol withdrawal syndrome. These findings do not rule out the possibility of a biochemical link between the action of ethanol and opiates at the level of opioid receptors.

Topics: Alcoholism; Animals; Diprenorphine; Female; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Seizures; Substance Withdrawal Syndrome

The slow potential change (spc) accompanying spreading depression (SD) was studied in rats and in a seizure-sensitive strain of Mongolian gerbil under three different experimental paradigms, each involving the use of naloxone. Gerbils undergoing electroconvulsive shock treatment displayed SD during the post-ictal phase, which was blocked by the intraperitoneal (i.p.) administration of naloxone (20-50 mg kg-1). Topical application of naloxone to the exposed cortex of the anaesthetized gerbil and rat blocked the spc of SD evoked by KCl. Microiontophoretic ejection of naloxone during extracellular recordings reversed cell refractoriness following the spc, demonstrated by the observation of a maintained sensitivity to iontophoretic pulses of glutamate. The results suggest a possible involvement of naloxone-sensitive processes in the mechanism responsible for cortical SD.

Topics: Animals; Bicuculline; Cerebral Cortex; Cortical Spreading Depression; Electroencephalography; Electroshock; gamma-Aminobutyric Acid; Gerbillinae; Glutamates; Glutamic Acid; Injections, Intravenous; Iontophoresis; Naloxone; Rats; Rats, Inbred Strains; Reaction Time; Seizures

The opioid receptor types involved in the mediation of enkephalin-induced electroencephalographic (EEG) seizures were studied in unanesthetized, freely moving rats. Four receptor-selective peptide ligands were evaluated for effectiveness in producing nonconvulsive EEG seizures after i.c.v. administration; these included the mu agonist, [D-Ala2-N-methyl-Phe4-Gly5-ol]enkephalin (DAGO), the mixed mu-delta agonist, [D-Ala2-D-Leu5]enkephalin (DADLE), and the selective delta agonists, [D-Pen2-D-Pen5]enkephalin and [D-Pen2-L-Pen5]enkephalin. Only DAGO and DADLE were found to produce EEG seizures, with DAGO being 9 times more potent than DADLE. DAGO produced a greater number of seizure episodes with a greater overall incidence compared with DADLE, reflecting its potent effect to elicit EEG seizure activity in these rats. Injections of [D-Pen2-D-Pen5]enkephalin or [D-Pen2-L-Pen5]enkephalin, even at the highest doses tested, failed to produce seizure activity. Behaviorally, the DAGO and DADLE EEG seizures were nonconvulsive but were temporally associated with episodic bursts of wet-dog shakes. The enkephalin-induced responses were extremely sensitive to antagonism by naloxone and completely blocked by pretreatment with the irreversible mu antagonist beta-funaltrexamine. The selective delta opioid receptor antagonist ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH) was ineffective. The use of the most selective agonists and antagonists for mu and delta opioid receptors suggests that, in rats, enkephalin-induced EEG seizures are mediated exclusively by mu opioid receptors and not by delta opioid systems.

Topics: Animals; Electroencephalography; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalins; Male; Naloxone; Naltrexone; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Seizures

In gerbils, the convulsive thresholds both for electroconvulsions and for pentetrazole-induced convulsions were increased when determined 15 min after a convulsion elicited by an air blast to the back of the animals. Contrary to a recently offered hypothesis, this sign of post-ictal depression could not be reversed by pretreatment with the morphine antagonists naloxone and naltrexone. This result speaks against a mediation of post-ictal depression by endogenous opioids.

Topics: Animals; Electric Stimulation; Endorphins; Gerbillinae; Morphine; Naloxone; Naltrexone; Pentylenetetrazole; Seizures

In mice, oxygen at hyperbaric pressures (515 kPa; 5 ATA) induces convulsions and lung damage (edema and hemorrhage). Morphine treatment (15 mg X kg-1, i.p.) significantly protects against the development of this pathology. The protection is abolished by naloxone (1 mg X kg-1, i.p.). Electric footshock, which induces diverse opioid effects, affords no protection against hyperbaric oxygen damage. Possible mechanisms of the morphine action are discussed.

Topics: Animals; Endorphins; Hyperbaric Oxygenation; Lung; Male; Mice; Mice, Inbred BALB C; Morphine; Naloxone; Oxygen; Seizures

Male Wistar rats implanted with bipolar electrodes in the amygdaloid complex were kindled. Subcutaneous injection of naloxone or naltrexone in low doses--0.12 and 0.24 mg/kg, respectively--dramatically reduced the postictal behavioural depression (BD) at 10 or 60 min. Remarkably, the BD was still reduced one day later. It would appear that the brain mechanisms involved in postictal BD use mu-receptors since BD is quite sensitive to low doses of the preferential antagonists naloxone and naltrexone. The long-term effects, the most novel aspect of these studies, are probably related to immediate effects but could be produced through slow genomic processes or alteration of the response to endogenously released enkephalins.

Topics: Amygdala; Animals; Behavior, Animal; Electric Stimulation; Kindling, Neurologic; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Seizures

Monosodium glutamate (MSG) administration to neonatal rodents produces convulsions and results in numerous biochemical and behavioral deficits. These studies were undertaken to determine if neonatal administration of MSG produced permanent alterations in seizure susceptibility, since previous investigations were inconclusive. A flurothyl ether seizure screening technique was used to evaluate seizure susceptibility in adult mice that received neonatal injections of MSG (4 mg/g and 1 mg/g). MSG treatment resulted in significant reductions in whole brain weight but did not alter seizure threshold. A naloxone (5 mg/kg) challenge was also ineffective in altering the seizure thresholds of either control of MSG-treated mice. Flurothyl ether produced hypothermia which was correlated with the duration of flurothyl exposure; however, the relationship of hypothermia to seizure induction was unclear. Flurothyl seizure testing proved to be a rapid and reliable technique with which to evaluate seizure susceptibility.

Topics: Animals; Body Temperature; Brain; Dose-Response Relationship, Drug; Flurothyl; Glutamates; Male; Mice; Mice, Inbred Strains; Naloxone; Organ Size; Seizures; Sodium Glutamate; Temperature

Graded seizure responses to suprathreshold cerebral electroshock in mice were modified by drugs acting at mu- and at delta-opioid receptors. Morphine exerts a proconvulsant effect at a non-mu opioid receptor and may exert a simultaneous anticonvulsant effect at a mu-opioid receptor. Delta-opioid receptor blockade increases seizure severity, suggesting a predominantly anticonvulsant nature of the delta-opioid system in the seizure model tested here.

Topics: Animals; Electric Stimulation; Enkephalin, Leucine; Epilepsy; Mice; Morphine; Naloxone; Narcotic Antagonists; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Seizures

Dynorphin A (1-13) acutely elevated the seizure threshold (ST) to the convulsant flurothyl, and this action was not blocked by naloxone. Increases in ST were also observed following i.c.v. injections of the non-opioid fragment dynorphin A (3-13). Pretreatment with dynorphin A (1-13), but not dynorphin A (3-13), non-competitively blocked the anticonvulsant effect of the mu selective opioid DAGO. Furthermore, pretreatment with dynorphin A (1-13) antagonized the delta antagonist properties of naloxone or ICI 154,129 in this seizure model. Thus, in addition to its non-opioid anticonvulsant effects, dynorphin A (1-13) exhibits unique antagonist actions which appear to be specific for the active opioid fragment.

Topics: Animals; Anticonvulsants; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Flurothyl; Male; Naloxone; Peptide Fragments; Rats; Rats, Inbred Strains; Seizures

In rabbits, pretreatment by intravenous (IV) and intracortical (IC) routes with low doses of morphine (250 micrograms/kg IV or 60 pmoles/rabbit IC) and naloxone (1-50 micrograms/kg IV or 0.3 pmoles/rabbit IC) antagonizes the EEG and behavioural seizures due to the IC injection of penicillin (150 Units) at the level of the sensorimotor cortex. Pretreatment with naloxone (20 micrograms/kg IV) did not alter the anticonvulsant effect of morphine (250 micrograms/kg IV). The similar anticonvulsant effect of the two drugs together with the absence of any antagonism by naloxone on the effect of morphine seem to suggest that both drugs act through a non-opioid receptor-mediated mechanism. Further, in light of the low effective doses of the drugs and of the absence of any additive effect after their combined administration, one might speculate that morphine and naloxone do not act through different pharmacological receptors. However, the presence of distinct EEG patterns with either morphine or naloxone, injected IC and IV, in animals fully protected against penicillin-induced seizures, does not seem to be in favour of the latter possibility.

Topics: Animals; Cerebral Cortex; Electroencephalography; Injections; Injections, Intravenous; Male; Morphine; Naloxone; Penicillins; Rabbits; Receptors, Opioid; Seizures

Topics: Adrenocorticotropic Hormone; Animals; Baclofen; Behavior, Animal; beta-Endorphin; Brain; Diazepam; Endorphins; gamma-Aminobutyric Acid; In Vitro Techniques; Injections, Intraventricular; Naloxone; Pain; Pituitary Gland; Rats; Receptors, GABA-A; Receptors, Opioid; Seizures; Zinc

In rats the influence of the delta opioid agonists [Leu]enkephalin, [D-Ala2-D-Leu5]enkephalin, [D-Ala2]methionine enkephalinamide and synthetic analogue of [Met]enkephalin: Tyr-D-Ala-Gly-Phe-D-Leu-OMe on audiogenic seizures was tested during ethanol abstinence. All investigated drugs significantly inhibited this ethanol withdrawal symptom. The results are compatible with the hypothesis of opioid involvement in the ethanol abstinence syndrome.

Topics: Acoustic Stimulation; Animals; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalin, Methionine; Ethanol; Female; Naloxone; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Seizures; Substance Withdrawal Syndrome

Increasing doses of naloxone hydrochloride (100-1000 nmol) were micro-injected unilaterally into the rat amygdala and the behavioral, neuropathological and electrographic responses were studied. Microinjections of low doses of naloxone (100-250 nmol) produced staring, gustatory automatisms and wet shakes whereas higher doses additionally resulted in motor limbic seizures and status epilepticus. The electroencephalogram showed a sequence of alterations characterised by high voltage fast activity, spiking, bursts of polyspiking, electrographic seizures and postictal depression which first appeared in the amygdala and rapidly spread to hippocampal and cortical areas. The neuropathological analysis of frontal forebrain sections by means of light microscopy revealed seizure-related brain damage in amygdala, olfactory cortex, thalamus, hippocampal formation, substantia nigra and neocortex. Diazepam, 10 mg/kg i.p., when given prior to the microinjection of naloxone into the amygdala, abolished the epileptogenic and neurotoxic effects of the drug. The results suggest that naloxone, when microinjected into rat amygdala elicits electrographic and motor limbic seizures followed by seizure-related brain damage.

Topics: Amygdala; Animals; Convulsants; Electroencephalography; Epilepsy; Male; Naloxone; Rats; Rats, Inbred Strains; Seizures

The ability of sulfhydryl compounds to provide protection against the acute toxicity of codeinone, a toxic metabolite of codeine, was investigated in mice. Subcutaneous administration of codeinone produced a slight reduction in hepatic glutathione concentration. Pretreatment of the mice with glutathione or cysteine significantly increased the survival rate for mice given a lethal dose of codeinone (10 mg/kg). The lethality of codeine was lowered by naloxone, whereas that of codeinone was not blocked by naloxone. The strychnine-like convulsant action of codeinone could be prevented by phenobarbital pretreatment. Glutathione pretreatment reduced the amounts of radioactivity in tissues of mice injected with [N-methyl-3-H]codeinone. A possible explanation for these observations is that glutathione reacts in vivo with codeinone and plays a role as a scavenger of this compound. This assumption is supported by the observation that codeinone reacts non-enzymatically with glutathione under physiological conditions.

Topics: Animals; Codeine; Glutathione; Male; Mice; Mice, Inbred Strains; Naloxone; Phenobarbital; Seizures; Tritium

Pregnant mice are more susceptible to flurothyl-induced seizures than are non-pregnant controls. The possibility that the well-known increase in beta-endorphin concentration which accompanies pregnancy was involved in this effect was examined by testing whether naloxone administration could block the increased seizure susceptibility. Pregnant female, control female and male C3H mice were treated with 5-50 mg/kg naloxone 5 min before flurothyl seizure testing. Naloxone markedly increased clonic seizure susceptibility in all three groups at a dose of 50 mg/kg, but had little effect at lower doses. In contrast, naloxone had differential effects on myoclonic seizures in pregnant and control female mice, being anticonvulsant in the controls, but proconvulsant in the pregnant mice. A role for endogenous opiates is unlikely in mediating clonic seizures in pregnant mice, but may be involved in myoclonic seizures.

Topics: Animals; Endorphins; Female; Flurothyl; Male; Mice; Mice, Inbred C3H; Naloxone; Pregnancy; Pregnancy Complications; Seizures

The effect of morphine pretreatment on kainic acid-induced seizures in rats was investigated by electroencephalographic recording. Seizure activity was quantified by counting the number of spikes in the EEG of freely-moving rats during 2 min periods at 30 min intervals after the intraperitoneal administration of 8, 10 or 12 mg/kg kainic acid. Pretreatment with morphine (1-10 mg/kg s.c.) 10 min before kainic acid administration significantly increased the number of spikes in the EEG in a dose-dependent manner. The potentiating effect of morphine on kainic acid-induced seizures was reduced considerably, but not abolished completely by pretreatment with naloxone (2-5 mg/kg s.c.). The results indicate that the potentiating action of morphine on kainic acid-induced seizures may be exerted in both a specific, naloxone-reversible manner and a non-specific, naloxone-resistant manner.

Topics: Animals; Dose-Response Relationship, Drug; Drug Synergism; Electroencephalography; Kainic Acid; Male; Morphine; Naloxone; Rats; Rats, Inbred Strains; Seizures

A patient with seizures, coma and respiratory depression after pentazocine overdose was treated successfully with naloxone and artificial ventilation. Pentazocine is an antagonist of the mu opioid receptors and a partial agonist of the kappa and sigma receptors. Because naloxone has less affinity for kappa and sigma receptors than for mu receptors, larger doses of naloxone are frequently required in the treatment of pentazocine overdose. Our case lends support to the view that large doses of the narcotic antagonist naloxone may be effective in pentazocine overdose.

Topics: Adolescent; Coma; Female; Humans; Naloxone; Pentazocine; Respiration, Artificial; Respiratory Insufficiency; Seizures

Cerebrospinal fluid taken from rats subjected to electroshock-induced seizures and injected into the cerebral ventricles of rats that had not been shocked increased the seizure threshold of the recipients. The anticonvulsant activity of the donor cerebrospinal fluid was antagonized by opioid antagonists and enhanced by peptidase inhibitors. These results suggest the existence of an endogenous anticonvulsant substance in rat cerebrospinal fluid, possibly opioid in nature, which is activated as a consequence of a seizure and which may play a critical role in postseizure inhibition.

Topics: Animals; Anticonvulsants; Electroshock; Enkephalin, Leucine; Male; Naloxone; Narcotic Antagonists; Peptide Hydrolases; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Seizures

Microinfusion of morphine sulfate (50 nmol), [d-Ala2]-Met-enkephalin (35 nmol) or dynorphin A 1-13 (1 nmol) bilaterally into the substantia nigra significantly attenuated seizures induced by maximal electroshock in rats. This action was accompanied by stereotyped behavioral hyperactivity. These anticonvulsant and behavioral effects were antagonized by systemic naloxone administration; neither effect was observed after intranigral microinjection of dynorphin A 1-17 amide (1 nmol). These results are consistent with a mu opiate receptor-mediated inhibition of substantia nigra efferent neurons, and with the proposal that bilateral inhibition of nigral efferents attenuates seizure propagation. However, intranigral morphine failed to alter the severity of i.v. bicuculline seizures, indicating that opiate-mediated inhibition in substantia nigra is distinct from that produced by gamma-aminobutyric acid.

Topics: Animals; Bicuculline; Electroshock; Enkephalin, Methionine; Male; Morphine; Naloxone; Narcotics; Rats; Rats, Inbred Strains; Receptors, GABA-A; Receptors, Opioid; Receptors, Opioid, kappa; Seizures; Substantia Nigra

Dose-response comparisons of the ability of the selective delta antagonist ICI 154,129 (12.5-50 nmol), the nonselective antagonist naloxone (29-290 nmol), and the irreversible selective mu antagonist beta-fNA (1.3-21 nmol) to alter the threshold response to DADLE or etorphine was studied in the rat flurothyl seizure test. DADLE (35 nmol, i.c.v.) and etorphine (122 nmol/kg, s.c.) both caused increases in seizure threshold which were differentially antagonized by pretreatment (i.c.v.) with the respective antagonists. For DADLE, only ICI 154,129 and naloxone produced a dose-related blockade of the increase in seizure threshold, with ICI 154,129 being more potent than naloxone. In contrast, the anticonvulsant action of etorphine was not antagonized by ICI 154,129 (50 nmol), but was blocked by a low dose of naloxone (29 nmol) or beta-fNA (21 nmol). In addition, prior occupancy of mu-sites with beta-fNA (21 nmol) significantly diminished the abilities of either ICI 154, 129 (50 nmol) or naloxone (290 nmol) to antagonize the anticonvulsant action of DADLE. The results of this study demonstrated that the effects of DADLE to increase seizure threshold in the rat were primarily mediated by activation of a delta-opioid receptor system. Furthermore, evidence has been provided for a functional interaction between delta and mu receptors in the opioid regulation of seizure threshold.

Topics: Animals; Anticonvulsants; Cerebral Ventricles; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Etorphine; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Seizures

Acute administration of morphine produced a protective effect on electroshock (ECS)-induced seizures in mice, while naloxone and naltrexone decreased ECS seizure threshold. Chronic morphine administration in mice resulted in a decrease of ECS-induced seizure threshold evident within 24 h following the end of drug treatment. This effect disappeared 5 days after the end of chronic morphine treatment. Moreover, tolerance to the anticonvulsant effect of morphine was evident in mice chronically treated with morphine and subjected to ECS 30 min after the last injection of the drug, as well as in mice subjected to ECS 24 h after the end of chronic treatment.

Topics: Animals; Electroshock; Endorphins; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Naltrexone; Receptors, Opioid; Seizures; Time Factors

Immediately following a seizure, the severity of subsequent seizures is significantly reduced. The involvement of endogenous opioid systems as a physiological regulator of this postseizure inhibition was studied in rats using repeated maximal electroshock (MES) seizures. Both the opiate antagonist (-)-naloxone and morphine tolerance abolished the progressive seizure protection associated with repeated MES. We propose that endogenous opioids, activated by a prior seizure, provide a central homeostatic inhibitory mechanism which may be responsible for the initiation of a postictal refractory state in the epileptic.

Topics: Animals; Drug Tolerance; Endorphins; Male; Morphine; Naloxone; Rats; Rats, Inbred Strains; Seizures

Systemic administration of morphine hydrochloride (MF; 5-80 mg/kg; i.p.) in rats enhanced the epileptogenic potential of pilocarpine hydrochloride (PIL) in a dose-dependent manner. PIL, 100 mg/kg; i.p., which did not result in convulsions by itself, produced sustained limbic seizures and epileptic brain damage in MF-pretreated rats. MF-induced enhancement of PIL neurotoxicity was blocked by naloxone hydrochloride (NAL; 2 and 10 mg/kg; i.p.). Administration of NAL (2-20 mg/kg) prior to PIL in the dose of 380 mg/kg moderately decreased the incidence of convulsions, brain damage and lethal toxicity produced by this agent. These results support the hypothesis that opiate mechanisms are involved in the maintenance of the threshold for propagation of seizure activity within limbic circuits.

Topics: Animals; Drug Interactions; Endorphins; Limbic System; Male; Morphine; Naloxone; Pilocarpine; Rats; Rats, Inbred Strains; Seizures

Electroconvulsive shock (ECS)-induced seizures present a clear cut diurnal rhythmicity when BALB/c mice are subjected to a light-dark (L/D) schedule. On the contrary, in the absence of external synchronizers no evident fluctuations in epileptic behaviour were evident. Naloxone decreased the threshold of ECS-induced convulsions, thus confirming an involvement of opioids in this type of behaviour. These findings indicate that opioids present a diurnal (L/D) but not circadian (L/L) rhythmicity in BALB/c mice.

Topics: Adaptation, Physiological; Animals; Brain; Circadian Rhythm; Electroshock; Endorphins; Mice; Mice, Inbred BALB C; Naloxone; Seizures

Topics: Animals; Disease Models, Animal; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Seizures

Acute i.c.v. administration of ICI 154,129 (100-600 micrograms), a delta-opioid receptor antagonist, raised the seizure threshold in a dose-related manner in rats exposed to flurothyl, a volatile convulsant. Pretreatment with naloxone or beta-funaltrexamine (beta-FNA) antagonized this effect. Lower doses of ICI 154,129 (12.5-50 micrograms), which did not influence seizure threshold, selectively antagonized the anticonvulsant action of [D-Ala2,D-Leu5]enkephalin (DADLE) in the same procedure. Consequently, it may be inferred that ICI 154,129 at high doses has mu-agonist and at low doses delta-antagonist properties in the rat flurothyl test.

Topics: Animals; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Seizures

The effects of repeated infusion of small, initially subconvulsive amounts of beta-endorphin, met-enkephalin or morphine sulfate into the amygdala and hippocampus were investigated. beta-endorphin and met-enkephalin evoked epileptiform spiking when infused into the posterior amygdala or ventral hippocampus. Morphine evoked epileptiform spiking when infused into the anterior amygdala. Naloxone blocked or terminated the spiking. Repetition of the infusions led to the gradual development of bilateral generalized convulsions by beta-endorphin and met-enkephalin and to the development of tolerance to morphine. An unexpected observation was that handling, immobilization or conspecific threat potentiated the epileptiform effects of beta-endorphin and morphine in many cases. These results suggest that endogenous opiate mechanisms might play a role in convulsive seizures and that stressful stimuli can exacerbate opiate seizures.

Topics: Animals; beta-Endorphin; Brain; Electroencephalography; Endorphins; Enkephalin, Methionine; Handling, Psychological; Kindling, Neurologic; Male; Morphine; Naloxone; Rats; Seizures

Rats ranging in postnatal age from 6 hours to 28 days were implanted with cortical and depth electrodes as well as an indwelling cannula in the lateral ventricle. We then administered varying amounts of the opiate peptides leucine-enkephalin and beta-endorphin intracerebroventricularly with continuous electroencephalographic monitoring. Leucine-enkephalin produced electrical seizure activity in rats as young as 2 days. beta-Endorphin administration was associated with seizures at the fifth postnatal day, with a high incidence of apnea resulting in death in animals as young as 6 hours. An adult seizure response to beta-endorphin and leucine-enkephalin was seen at 15 and 28 days of age, respectively. Naloxone blocked the seizure produced by these opiate peptides in all age groups. The data indicate that the opiate peptides are potent epileptogenic compounds in developing brain, that seizures induced by leucine-enkephalin differ from those caused by beta-endorphin, and that petit mal-like seizure activity can be an adult response in the rodent.

Topics: Aging; Animals; beta-Endorphin; Brain; Electroencephalography; Endorphins; Enkephalin, Leucine; Evoked Potentials; Male; Naloxone; Rats; Rats, Inbred Strains; Seizures

In order to elucidate the relationship between REM sleep and the enkephalinergic system, the effects of REM sleep deprivation (REMSD), stress and the enkephalinase inhibitor phosphoramidon on handling-induced convulsions were studied in mice. REMSD, stress and phosphoramidon (25-500 micrograms icv) increased the frequency of handling-induced convulsions (HIC) in normal mice. However, only in the last two groups were HIC antagonized by naloxone (1 mg/kg IP). In REMSD mice, phosphoramidon decreased the frequency of HIC, this effect being abolished by naloxone. The increase of neuronal excitability during REMSD is suggested to be associated with an insufficiency of the enkephalinergic system.

Topics: Animals; Disease Susceptibility; Glycopeptides; Handling, Psychological; Humans; Male; Mice; Mice, Inbred Strains; Naloxone; Neprilysin; Protease Inhibitors; Seizures; Sleep Deprivation; Sleep, REM; Stress, Psychological

The influence of centrally administered meperidine, normeperidine and pentazocine on the excitability of brain was studied by measuring the threshold for flurothyl-induced convulsions in rats. All three opioids are reported to lower seizure thresholds when given subcutaneously to rats in this test. Dose-and time-dependent changes in the seizure threshold occurred after intracerebroventricular injection of pentazocine (10-160 micrograms), meperidine (25-150 micrograms) and normeperidine (50-150 micrograms). Rapid increases in the seizure threshold were associated with pentazocine and meperidine, whereas a slowly developing decrease in the threshold was caused by normeperidine. Naloxone (10 mg/kg, s.c.) antagonized the anticonvulsant effect of meperidine (but not that of pentazocine) and enhanced the proconvulsant effect of normeperidine. Thebaine (25-150 micrograms), which had no marked influence on the seizure threshold when given intracerebroventricularly, lowered the threshold after subcutaneous injection of 12.5 and 25 mg/kg. This effect was not altered by injection of naloxone. These results show that centrally administered opioids can act on excitatory or inhibitory systems that regulate seizure mechanisms in the rat brain. Furthermore both naloxone-sensitive and naloxone-insensitive components are involved. Meperidine, pentazocine and thebaine have different actions on the seizure threshold after intracerebroventricular, as opposed to subcutaneous, administration. This work has, therefore, identified the route of administration as a critical variable in the effect of opioids on the seizure threshold in rats.

Topics: Animals; Brain; Dose-Response Relationship, Drug; Flurothyl; Injections, Intraventricular; Male; Meperidine; Naloxone; Narcotics; Pentazocine; Rats; Rats, Inbred Strains; Seizures; Thebaine

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 regulation 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.

Topics: Animals; Anticonvulsants; Cerebral Cortex; Cyclazocine; Electroencephalography; Male; Morphine; Naloxone; Penicillins; Rabbits; Seizures; Strychnine

Intoxicated persons appear frequently in substance abuse centers and in general hospital settings. The severity of their condition ranges from mild impairment to coma or delirium. The prominent features of intoxication with the major classes of abused drugs are described. Staff responses to intoxication are discussed. Guidelines are presented for systematic management of this condition.

Topics: Arrhythmias, Cardiac; Delusions; Diazepam; Hallucinations; Hallucinogens; Humans; Hypnotics and Sedatives; Naloxone; Narcotics; Nonprescription Drugs; Phencyclidine; Poisoning; Seizures; Solvents; Stimulation, Chemical

The incidence of withdrawal convulsions was determined in mice following removal from a 70 per cent nitrous oxide environment. Groups of 20 mice received saline (control), naloxone or morphine subcutaneous injections five minutes prior to withdrawal. The observer was blind to the treatments. In comparison to the control group, the proportion convulsing was significantly (p less than 0.05) increased following naloxone 0.125 mg (n = 40), 0.25 mg, but not 0.5 mg. The proportion convulsing was significantly decreased following morphine 0.4 mg. Overall proportions of mice convulsing was 0.55 for the saline control group; 0.73 for naloxone 0.125 mg; 0.80 for naloxone 0.25 mg; 0.60 for naloxone 0.50 mg; and 0.38 for morphine 0.4 mg. Modification of this phenomenon by both an opiate antagonist and agonist suggests endorphin withdrawal as a possible mechanism. However, this should be regarded as indirect evidence pending further study of this area.

Topics: Animals; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Nitrous Oxide; Receptors, Opioid; Seizures; Sodium Chloride; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Brain; Convulsants; Electroencephalography; Electrophysiology; GABA Antagonists; Morphine; Naloxone; Narcotics; Nikethamide; Pentylenetetrazole; Seizures; Strychnine; Synaptic Transmission

Two experiments were conducted to investigate the effects of naloxone hydrochloride on seizure thresholds seizure afterdischarges (thresholds and durations) and on post-ictal depression. Experiment 1 examined the effects of naloxone dosage and interstimulation interval (ISI) on kindled seizures. Eight male hooded rats were exposed to a factorial combination of two ISIs (30 and 60 s) and 3 naloxone doses (2, 10 mg/kg and a saline control) during a threshold testing procedure. Naloxone was found to significantly shorten motor seizure duration and post-ictal depression. Experiment 2 examined the effects of naloxone on a subsequent suprathreshold-stimulation-induced seizure following an initial suprathreshold stimulation. A factorial combination of 3 naloxone doses (2, 5 and 10 mg/kg) and a saline control and two ISIs (2 and 6 min) separating the two stimulations was employed. While no main effects for either naloxone or ISI were found in the subsequent seizure activity, there was a significant interaction between naloxone and ISI for the subsequent motor seizure duration. It was concluded from the results of the present experiments that the direction and consistency of naloxone's effects on kindled seizures were present but not very strong. However, the effects of ISI on seizure activity were found to be consistent with the previous literature.

Topics: Animals; Cortical Spreading Depression; Electric Stimulation; Kindling, Neurologic; Male; Motor Activity; Naloxone; Rats; Seizures; Stereotaxic Techniques

To learn more about postictal behaviors and their underlying mechanisms, five behaviors and EEG recordings were studied following fully generalized, kindled seizures in rats. The behaviors included bar pressing for food; tail withdrawal, squeak, and multiple squeak responses to painful tail shocks; consumption of freely available food; clinging to a vertical grid; and locomotion. Latencies from the end of a seizure afterdischarge until each behavior recovered were compared and were found to cluster in three distinct pairs. Locomotion and grid clinging recovered most quickly; consumption of freely available food and EEG postictal depression recovered next; and bar pressing for food and the multiple squeak response recovered most slowly. Naloxone pretreatment (10 mg/kg but not 1 mg/kg) shortened recovery to multiple squeak responses, grid clinging, and locomotion, without affecting recovery of bar pressing, food consumption, or EEG postictal depression. These results suggest that complex behaviors recover more slowly following a seizure than simple behaviors. It also appears that opioids are released by a kindled seizure and mediate certain postictal changes in motor- and pain-related behaviors.

Topics: Animals; Behavior, Animal; Electroencephalography; Kindling, Neurologic; Male; Movement; Naloxone; Rats; Rats, Inbred Strains; Seizures

Topics: Animals; Anticonvulsants; Chemical Phenomena; Chemistry; Electroshock; Hydantoins; Male; Mice; Naloxone; Pentylenetetrazole; Seizures

Morphine was administered by the intracerebroventricular (i.c.v.) route to pentobarbital-anesthetized rabbits. Small doses of morphine (less than 150 micrograms) potentiated, but larger doses (greater than 250 micrograms) shortened, the duration of anesthesia. In naltrexone-pretreated animals, all doses of morphine employed acted only as an analeptic. Atropine, but not atropine methylbromide, blocked the analeptic effect of morphine, indicating that a central cholinergic mechanism was involved in this response. Tolerance to the analeptic effect was not evident. These results suggest that morphine exerts an arousal action which is usually masked by the dominant narcotic properties, but which becomes evident when administered intracerebroventricularly or in the presence of naltrexone.

Topics: Anesthesia; Animals; Atropine; Behavior, Animal; Electroencephalography; Male; Morphine; Naloxone; Naltrexone; Pentobarbital; Rabbits; Seizures

In a naloxone-reversible, dose-dependent manner, morphine (10-50 mg/kg i.p.) protected against seizures induced by maximal electroshock and increased the incidence and severity of seizures induced by bicuculline, in rats. Morphine also potentiated seizures induced by isoniazid and by picrotoxin. Thus, opiate activity influences the expression of seizures in contrasting ways depending upon the mode of seizure induction. Since morphine consistently potentiated seizures induced by interference with GABA transmission, it appears that GABAergic systems may be of particular significance for the elucidation of the varied effects of morphine on seizure susceptibility.

Topics: Animals; Bicuculline; Drug Synergism; Electroshock; GABA Antagonists; Isoniazid; Male; Morphine; Naloxone; Picrotoxin; Rats; Rats, Inbred Strains; Seizures

Electrically induced seizures were followed by temporary elevations in serum prolactin over baseline in rats, while electrical irritation made no change. Naloxone 4 mg/kg i.p. pretreatment preserved this pattern but attenuated all levels including baseline by about 50%. While atropine 0.1 mg/kg s.c. did not change baseline levels, the prolactin levels after electrical irritation without seizure were about the same as those following a genuine seizure; atropine apparently facilitated stress-induced prolactin release. Seizures did not raise post-haloperidol prolactin levels above their high baseline levels.

Topics: Animals; Atropine; Electric Stimulation; Haloperidol; Male; Naloxone; Prolactin; Rats; Rats, Inbred Strains; Seizures

The nitrous oxide withdrawal syndrome in mice was used as an experimental model to examine some of the factors which may play a role in postanesthetic excitation. Predisposition to nitrous oxide withdrawal convulsions as judged by duration of susceptibility was decreased significantly after pretreatment with the cholinesterase inhibitors, physostigmine and galanthamine, or with the opiate receptor blocking agent naloxone. Results are discussed in relation to the central anticholinergic syndrome, endorphin release, and disturbances which follow nitrous oxide anesthesia in humans and animals.

Topics: Animals; Brain; Endorphins; Galantamine; Humans; Male; Mice; Naloxone; Nitrous Oxide; Parasympathetic Nervous System; Physostigmine; Seizures; Substance Withdrawal Syndrome

This study investigated the effect of naloxone on amnesia produced by subseizure amygdaloid stimulation. Animals were trained in an inhibitory avoidance task, and given amygdaloid stimulation following training. Immediately after training, prior to stimulation, naloxone was injected either peripherally (i.p.) or into the bed nucleus of the stria terminalis (BNST) where the Met-enkephalin-containing fibers from the amygdala terminate. Amygdaloid stimulation caused retention deficits. The deficits were attenuated by 3.0 mg/kg naloxone given peripherally or by 1.0 microgram or 0.3 microgram naloxone injected bilaterally into the BNST. The attenuative effect was anatomically and receptor specific: 0.3 microgram of naloxone injected into the caudate nucleus was ineffective; the attenuative effect of naloxone was antagonized by simultaneous injection of 1.5 or 4.5 micrograms levorphanol into the BNST. These results suggest that endogenous opioids, possibly the enkephalins of the stria terminalis released into the BNST following amygdaloid stimulation, are at least partially involved in mediating the effect of amygdaloid stimulation on memory.

Topics: Amnesia; Amygdala; Animals; Avoidance Learning; Electric Stimulation; Humans; Male; Naloxone; Rats; Rats, Inbred Strains; Seizures

Topics: Aged; Brain Ischemia; Female; Humans; Naloxone; Seizures

Narcotic withdrawal was precipitated by administration of naloxone in a low dose at 2 h after the final dose of morphine in a 9-day dependency-inducing schedule. Withdrawal was characterized by leaps, increased nocifensor activity and by cerebral cortical epileptiform activity, the latter not generally reported to be prominent in narcotic withdrawal. Single large doses of morphine did not provoke epileptiform activity at 2 h postinjection but did induce an acute opioid dependency wherein a moderately high dose of naloxone, ineffective in non-dependent rats, provoked upward leaping and electrocortical epileptiform activity. Pretreatment of the 9-day dependent rats with peptidase inhibitors, administered intracerebroventricularly, significantly reduced withdrawal severity including the epileptiform activity. We propose that peptidase inhibitors protect certain species of endogenous opioids and/or other neuropeptides that tend to suppress expression of the narcotic withdrawal syndrome. Furthermore, our findings suggest that epileptiform activity is a nascent form of cerebral activity hitherto largely unnoticed in narcotic withdrawal and that neuropeptides may be involved in certain epileptic states.

Topics: Animals; Aprotinin; Behavior, Animal; Humans; Male; Morphine; Naloxone; Rats; Rats, Inbred Strains; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Behavior, Animal; Body Temperature; Chlordecone; DDT; Dieldrin; Dose-Response Relationship, Drug; Drug Interactions; Female; Insecticides; Naloxone; Nervous System Diseases; Organ Size; Rats; Rats, Inbred Strains; Seizures

Kainic acid (KA) is a potent convulsant which, when administered subcutaneously, induces sustained limbic seizures and a pattern of limbic brain damage that is thought to be seizure-mediated. Diazepam suppresses and morphine enhances both the seizures and brain damage induced by KA. Here we show that morphine enhancement of KA neurotoxicity is blocked in a dose-dependent manner by subcutaneous pretreatment with naloxone. Theses and related findings support the hypothesis that morphine enhances the seizure-linked neurotoxicity of KA by an opiate specific action at certain limbic receptor sites where opiates suppress GABAergic activity, thereby lowering the threshold for propagation of seizure activity in limbic circuits.

Topics: Animals; Brain; Kainic Acid; Male; Morphine; Naloxone; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, GABA-A; Seizures

Our laboratory previously suggested that opioid peptides are released by an amygdaloid kindled seizure and may affect the elicitation of a subsequent seizure. The present study examined the effects of morphine, naloxone, enkephalin analogues, and conditions of morphine tolerance and withdrawal on the severity and duration of a series of amygdaloid kindled seizures. The results suggest two distinct opiate/opioid actions on seizures. The first is an anticonvulsant effect on the behavioral manifestations of seizures. This effect is seen following a high dose (50 mg/kg) of morphine or a low dose (6 mg/kg) of enkephalin analogue (LY146104), and is reversed by naloxone. The second is a naloxone-reversible prolonging effect of the high dose of morphine on the electrographic components of the seizures. Receptor affinities of these various opiate/opioid drugs suggest that these two actions are mediated by different receptors which appear not to include high affinity mu receptors.

Topics: Animals; Behavior, Animal; Drug Tolerance; Enkephalins; Guinea Pigs; Humans; Kindling, Neurologic; Male; Mice; Morphine; Morphine Derivatives; Naloxone; Narcotics; Rats; Rats, Inbred Strains; Seizures; Substance Withdrawal Syndrome; Vas Deferens

Topics: Animals; Anticonvulsants; Brain; Convulsants; Electroencephalography; Endorphins; Morphine; Naloxone; Rats; Seizures

Opiate alkaloid and opioid peptide actions on spontaneous neuronal activity and postsynaptic amino acid responsiveness were assessed using intracellular recording techniques applied to murine spinal cord neurons in primary dissociated cell culture. Application of opiates was by superfusion and amino acids by iontophoresis. Glycine and GABA but not glutamate responses were antagonized by the opiate alkaloids. Since opiate effects on glycine and GABA responses were not naloxone-reversible, only weakly stereospecific, and not produced by the opioid peptide [D-Ala2]-Met-enkephalinamide, it is unlikely that these effects were mediated by opiate receptors. Opiate depression of glycine inhibition was correlated with the induction of paroxysmal depolarizations in cultured spinal cord neurons, suggesting that antagonism of inhibitory amino acid transmission may underlie the convulsant actions of high concentrations of the opiate alkaloids.

Topics: Animals; Cells, Cultured; Dextrorphan; Enkephalin, Methionine; Enkephalins; Evoked Potentials; gamma-Aminobutyric Acid; Glycine; Levorphanol; Mice; Morphine; Naloxone; Narcotics; Neural Inhibition; Neurons; Seizures; Spinal Cord; Synapses

Topics: Animals; Biological Assay; Calcium Chloride; Convulsants; Dose-Response Relationship, Drug; Guinea Pigs; Ileum; Isoquinolines; Mice; Muscle Contraction; Naloxone; Narcotics; Paralysis; Salsoline Alkaloids; Seizures; Tetrahydroisoquinolines

Intracerebroventricular (i.c.v.) injections of the endorphins and of morphine in rats produce highly characteristic, naloxone sensitive, electrographic seizures. In contrast, systemic injections of morphine have been shown to exert a marked anticonvulsant effect. The present study demonstrates that systemic morphine pretreatment can prevent the occurrence of electrographic seizures injected by i.c.v. morphine, Leu-enkephalin and beta-endorphin and that the anti-epileptic effect of morphine can be reversed by naloxone. Male albino rats, previously prepared for chronic i.c.v. injections and EEG recordings, were pretreated with 0--100 mg/kg of intraperitoneal (i.p.) morphine. Thirty five minutes later morphine (520 nmol), Leu-enkephalin (80 nmol) or beta-endorphin (5 nmol) were injected i.c.v. Pretreatment with i.p. morphine blocked the occurrence of seizures induced by morphine and both endogenous opioids. Lower doses of systemic morphine (50 mg/kg) were necessary to block i.c.v. morphine seizures than the dose (100 mg/kg) necessary to block seizures induced by i.c.v. Leu-enkephalin and beta-endorphin. Naloxone (1 mg/kg) administered 25 min following 50 mg/kg of i.p. morphine and preceding the injections of i.c.v. morphine reversed the antiepileptic effect of systemic morphine. These results demonstrate the possible existence of two opiate sensitive systems, one with excitatory-epileptogenic effects and the other possessing inhibitory-antiepileptic properties. The possible relationship between these findings and the known heterogeneity of opiate receptors and opiate actions is discussed.

Topics: Animals; Endorphins; Injections, Intraventricular; Male; Morphine; Naloxone; Narcotics; Rats; Rats, Inbred Strains; Seizures

Naloxone injected into the lateral septum caused intense electrocortical seizures which did not occur following callosal or periaqueductal gray (PAG) injections. Conversely, injections into periaqueductal gray caused a characteristic and pronounced backward circling with only moderate electrocortical changes. Intracerebral injection of naloxone had effects, including epileptogenesis, which appeared to be site-specific. These effects are in some ways similar to the effects of enkephalin and morphine.

Topics: Animals; Behavior, Animal; Brain; Convulsants; Electroencephalography; Male; Naloxone; Rats; Rats, Inbred Strains; Seizures

Brief electrical stimulation of the enkephalin-rich globus pallidus at 1-h intervals produced kindled, clonic seizures in rats as rapidly as similar stimulation of the amygdala. Massing the kindling trials at 10-min intervals inhibited the occurrence of subsequent seizures, especially following globus pallidus stimulation. Naloxone (20 mg/kg), an opiate receptor antagonist, reversed this post-ictal inhibition of seizures following massed trials, but had no effect on seizures kindled at 1-h intervals. Thus, endorphin-released during seizures do not appear to mediate the production of kindled seizures, but do appear to mediate the transient posts ictal inhibition of seizures.

Topics: Amygdala; Animals; Enkephalins; Globus Pallidus; Kindling, Neurologic; Male; Naloxone; Rats; Rats, Inbred Strains; Reflex; Seizures

Topics: Amygdala; Analgesia; Animals; Behavior, Animal; Electroshock; Kindling, Neurologic; Male; Naloxone; Pain; Rats; Rats, Inbred Strains; Seizures

Mice which have been selectively bred for differences in sensitivity to acute doses of alcohol have also been shown to differ in severity of seizures upon withdrawal from chronic alcohol administration. We investigated the responsiveness of these mice to withdrawal from chronic morphine treatment. Mice were made dependent on morphine via pellet implantation, and withdrawal was precipitated with naloxone challenge. Mice which are less sensitive to the hypnotic effects of ethanol (short sleep: SS) displayed more jumping and wet dog shakes during withdrawal than did the more sensitive long sleep (LS) mice. In addition, the amount of jumping was dependent on the dose of naloxone in both lines. Differences between lines in naloxone precipitated withdrawal may reflect differences in alterations in extrapyramidal dopaminergic activity, but other substrates for the observed differences cannot be discounted. Finally, the observed difference between SS and LS mice in severity of morphine withdrawal parallels the previously reported difference between these lines in seizure severity during withdrawal from alcohol.

Topics: Alcoholism; Animals; Behavior, Animal; Humans; Mice; Mice, Inbred Strains; Morphine; Morphine Dependence; Naloxone; Seizures; Substance Withdrawal Syndrome

Topics: Animals; Electric Stimulation; Endorphins; Naloxone; Pain; Peptides; Rats; Receptors, Opioid; Seizures

Topics: Animals; Anticonvulsants; beta-Endorphin; Dose-Response Relationship, Drug; Endorphins; Enkephalin, Methionine; Enkephalins; Etorphine; Flurothyl; Male; Morphinans; Naloxone; Rats; Rats, Inbred Strains; Seizures; Structure-Activity Relationship

Mice of two strains, Crl:CD-1(1CR)Br and C57BL6, were exposed to nitrous oxide at concentrations of 50, 65 and 80 per cent for 34 or 68 hours. Cessation of nitrous oxide resulted in characteristic convulsions similar to those seen in alcohol withdrawal in all mice. These peaked in severity within 2-3 minutes after removal from nitrous oxide and declined over 6 hours. The severity and duration of these convulsions were related to the nitrous oxide concentration and duration of exposure. Naloxone or naltrexone produced no significant increase in severity of convulsions. The narcotic antagonists did not precipitate acute weight loss or characteristic jumping behaviour seen in animals dependent on opiates. These results demonstrate that chronic exposure to nitrous oxide results in development of physical dependence which resembles alcohol and not opiate dependence. Analgesia and physical dependence produced by nitrous oxide appear to be mediated through separate mechanisms.

Topics: Animals; Ethanol; Humans; Male; Mice; Naloxone; Nitrous Oxide; Opioid-Related Disorders; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Apomorphine; Behavior, Animal; Catalepsy; Catatonia; Electric Stimulation; Female; Haloperidol; Humans; Naloxone; Rats; Seizures

Topics: Amygdala; Animals; Anticonvulsants; Diazepam; Electric Stimulation; Male; Melatonin; Naloxone; Pentylenetetrazole; Phenobarbital; Rats; Seizures

The electroencephalographic effects of a range of doses of naloxone were evaluated in an effort to address the apparent epileptogenic properties of the drug. Electrographic activity was recorded from epidural electrodes in eight monkeys. The records were visually inspected and subjected to power spectral analyses. Concurrent visual evoked potentials were recorded and analyzed by standard procedures. Large doses (greater than 32.0 mg/kg i.m.) of naloxone were quickly and reliably succeeded by high voltage electrographic seizure activity at cortex. Lower doses (greater than or equal to 8.0 mg/kg) were followed by increased voltage in high frequency electroencephalogram (EEG) and spiking activity. Visual evoked potential latencies were reliably extended. As determined by power spectral analyses and third order slope analyses, the drug effects on EEG were related to time and dose. The early effects of high doses mimicked the maximal effects of low doses. It is concluded that seizures which follow high doses (48.0--64.0 mg/kg) of naloxone are derived from changes which are evident after doses which approach those used clinically to antagonize opiates. Such changes are, however, not readily apparent under visual inspection of the EEG.

Topics: Animals; Dose-Response Relationship, Drug; Electroencephalography; Female; Macaca; Male; Naloxone; Seizures; Time Factors

FK-33,824 (Tyr-D-Ala-Gly-MePhe-Met(O)-ol) and metkephamid (Tyr-D-Ala-Gly-Phe-N(Me)Met-CONH2; LY 127623) are two parenterally active synthetic analogues of the endogenous morphinomimetic pentapeptide, [Met5]-enkephalin. Acute s.c. administration of each analogue raised the seizure threshold in a dose-related manner in rats challenged with flurothyl, a volatile convulsant. The anticonvulsant action was antagonized by a low dose of naloxone (0.10 mg/kg s.c.). FK-33,824 and metkephamid can therefore be classified with typical mu-receptor agonists such as morphine and etorphine in this procedure.

Topics: Animals; Anticonvulsants; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Dose-Response Relationship, Drug; Endorphins; Enkephalin, Methionine; Enkephalins; Flurothyl; Male; Naloxone; Rats; Seizures

Rats were studied (a) after a single transauricular electroshock (acute ECS) and (b) following 10 consecutive once-daily shocks (chronic ECS). ECS produced a generalized convulsion marked by a polyspike EEG seizure. The seizure was followed by a period of postictal depression (PID) characterized by EEG high-voltage synchrony, EMG quietening, and an associated stuporous behavior in the rat. Acute ECS produced a maximal of 33 +/- 8 (S.E.) percent above control in the EEG voltage output during postictus, with the PID lasting 2680 +/- 658 sec. Chronic ECS resulted in a significant enhancement of these acute responses. Pretreating rats with naloxone (0.3-10 mg/kg s.c.) antagonized the postictal effects of acute ECS, but not of chronic ECS. These naloxone-sensitive postictal EEG and behavioral changes appear to reflect a release of endogenous opioid peptides during ictus, a finding consistent with the hypothesis that electroshock activates opioid systems.

Topics: Animals; Behavior, Animal; Electroconvulsive Therapy; Electroencephalography; Electromyography; Endorphins; Male; Naloxone; Rats; Rats, Inbred Strains; Seizures

Topics: Amygdala; Animals; Electric Stimulation; Male; Morphine; Naloxone; Pain; Rats; Reaction Time; Seizures; Tail

Topics: Animals; Brain; Electroencephalography; Endorphins; Ethanol; Evoked Potentials; Haplorhini; Male; Naloxone; Seizures

Electrographic seizure activity was recorded shortly following naxolone injections in artificially ventilated, methadone-treated stump-tailed macaques. Plasma-methadone concentrations prior to seizure activity were many times higher than those that have produced respiratory depression and death in nonventilated monkeys. The duration of seizure activity was clearly related to the dose of naloxone. Naloxone was without epileptogenic properties in animals that had not been pretreated with methadone. The results suggest that methadone and naloxone have additive epileptogenic properties when high blood levels of methadone are achieved in the artificially ventilated primate. Naloxone was devoid of antagonistic properties with respect to opiate-induced electroencephalographic spiking activity.

Topics: Animals; Blood Pressure; Body Temperature; Drug Interactions; Electrocardiography; Electroencephalography; Female; Haplorhini; Macaca; Male; Methadone; Naloxone; Seizures; Time Factors

Topics: Amygdala; Animals; Electric Stimulation; Evoked Potentials; Female; Morphine; Naloxone; Rats; Seizures

The severity of audiogenic seizures was increased in two strains of mice 5--10 min after naloxone (2 or 4 mg/kg IP). This may indicate involvement of an endorphin or enkephalin in the modulation of reactivity.

Topics: Acoustic Stimulation; Animals; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Naloxone; Seizures; Species Specificity; Stimulation, Chemical

Intracerebroventricular administration of 10--20 microgram of steroid-O-sulfates induced hypermotility, agitation, salivation, EEG abnormalities, stereotypies, wet dog shakes and seizures. Equivalent effects resulted from 30--200 microgram morphine sulfate (H2SO4 salt), 50 microgram EGTA or 300--400 microgram of sodium sulfate or phosphate, but not chloride, nitrate or acetate. Non-steroid sulfates, steroid glucuronides and steroid phosphates were inactive. Naloxone, previously found to antagonize the excitatory effects of androsterone sulfate, failed to antagonize those of cortisol sulfate, sodium sulfate or EGTA. These findings suggest a role for extracellular calcium ions and for sulfate derived from circulating steroids in central responses to opiates.

Topics: Aggression; Animals; Behavior, Animal; Brain; Calcium; Chelating Agents; Dose-Response Relationship, Drug; Electroencephalography; Evoked Potentials; Humans; Injections, Intraventricular; Male; Morphine; Naloxone; Rats; Receptors, Opioid; Seizures; Steroids; Sulfates

Topics: Amygdala; Animals; Behavior, Animal; Electric Stimulation; Electroencephalography; Endorphins; Enkephalins; Evoked Potentials; Morphine; Naloxone; Rats; Receptors, Opioid; Seizures

The effects of intracerebroventricular (i.c.v.) or systemic injections of Met- or Leu-enkephalin, beta-endorphin, FK 33.824 (D-Ala2, MePhe4, Met(O5)-ol-enkephalin) and of morphine and naloxone have been studied in baboons, Papio papio, which spontaneously show photically induced epileptic responses. Animals were chronically implanted with epidural or deep recording electrodes and a cannula in one lateral ventricle, and tested whilst seated in a primate chair. In some animals the natural syndrome was enhanced by the prior administration of DL-allylglycine, 100--200 mg/kg, i.v. Met- or Leu-enkephalin, 1--10 mg, i.c.v., did not lead to any manifest focal or generalized seizure discharges. Nor did it lead to any consistent enhancement or reduction of photically induced myoclonic responses (as tested 5--10 min after injection). beta-Endorphin, 0.1--0.5 mg, i.c.v., did not enhance or impair photically induced myoclonic responses. FK 33.824, 0.1--0.5 mg, i.c.v., depressed respiration and slowed EEG background rhythms for 9--15 h. This was associated with a loss of myoclonic responses to photic stimulation. These effects were reversed for 20--40 min following the injection of naloxone, 1 mg/kg i.m. A depression of respiration and a slowing of EEG rhythms was seen beginning 5--20 min after FK 33.824, 2 or 4 mg/kg, i.v. The higher dose also abolished photically induced myoclonic responses. Naloxone, 1 mg/kg, definitively reversed these effects. Morphine, 5--10 mg i.c.v., tended to increase the latency to onset of generalized myoclonus during photic stimulation. Myoclonic responses were delayed or diminished after morphine, 5 mg/kg, i.m. Naloxone, 1--2 mg/kg i.m., reversed this effect. Naloxone, 0.2--5.0 mg/kg i.m., alone, did not significantly modify photically induced myoclonus, either in animals of low or high initial responsiveness, or in those pretreated with allylglycine.

Topics: Animals; Blood Pressure; Cerebral Cortex; Electroencephalography; Endorphins; Enkephalins; Evoked Potentials; Haplorhini; Injections, Intramuscular; Injections, Intraventricular; Morphine; Myoclonus; Naloxone; Papio; Photic Stimulation; Receptors, Opioid; Respiration; Seizures; Thalamic Nuclei

Alcohol has been reported to produce a significant reduction in the brain calcium content of rats, which could be blocked by administration of naloxone. Ethanol pretreatment failed to decrease brain cortex calcium and, in fact, increased the calcium content at higher doses. The effects of naloxone were also studied.

Topics: Animals; Brain; Calcium; Corticosterone; Dose-Response Relationship, Drug; Drug Interactions; Ethanol; Hydroxyindoleacetic Acid; Male; Mice; Mice, Inbred C57BL; Naloxone; Seizures; Time Factors

Topics: Amygdala; Animals; Caudate Nucleus; Electric Stimulation; Male; Naloxone; Rats; Seizures

Topics: Animals; Brain; Dose-Response Relationship, Drug; Kainic Acid; Male; Morphine; Naloxone; Pyrrolidines; Rats; Seizures

Topics: Analysis of Variance; Animals; Atropine; Barium; Lethal Dose 50; Male; Mice; Models, Biological; Naloxone; Seizures

Topics: Amygdala; Animals; Electric Stimulation; Male; Morphine; Naloxone; Premedication; Rats; Seizures

Twenty opioids have been subdivided into four classes by using flurothyl-induced seizures in rats to measure dose-response relationships, stereospecificity, naloxone sensitivity, and tolerance-cross-tolerance. The data support current theories of multiple opiate receptor types. Since the receptors involved mediate effects that are antagonized, enhanced, or unaffected by naloxone, the model is uniquely suitable for detecting novel narcotic antagonists that can then be used to differentiate opiate receptors in other systems.

Topics: Animals; Drug Tolerance; Flurothyl; Male; Meperidine; Naloxone; Narcotics; Pentazocine; Rats; Seizures; Stereoisomerism

Topics: Animals; Behavior, Animal; Body Temperature Regulation; Endorphins; Hypothalamus; Male; Naloxone; Postural Balance; Rats; Reflex; Salivation; Seizures; Thyrotropin-Releasing Hormone

Single injections of 120 micrograms of methionine-enkephalin were made into various midbrain and forebrain structures in the rat. Analgesia was observed after injections into or near the ventral, caudal midbrain periaqueductal gray matter. Seizures and other pathological electroencephalogram (EEG) changes were seen with injections into or near the forebrain dorsomedial nucleus of the thalamus. No animals with midbrain injection sites showed EEG changes, and none with forebrain injection sites were analgesic. These data, taken together with other lines of evidence, suggest that enkephalin-induced analgesia and enkephalin-induced seizures are mediated by opiate receptors that are located in different brain areas and that are pharmacologically different.

Topics: Analgesia; Animals; Brain; Cerebral Aqueduct; Dose-Response Relationship, Drug; Endorphins; Enkephalins; Male; Naloxone; Rats; Receptors, Opioid; Seizures; Thalamic Nuclei

Morphologically similar epileptic seizures were recorded from the cortex of rats after injections into the lateral ventricle of 100 microgram of leucine-enkephalin, methionine-enkephalin, and morphine. Seizures were either greatly attenuated or blocked completely by prior systemic administration of naloxone (10 mg/kg). These findings suggest that such seizures result from an interaction of these compounds with opiate receptors in the brain. The epileptogenic potency of the enkephalins was illustrated by the observation that seizures and other pathological manifestations could still be elicited by doses as low as 10 microgram. Leucine-enkephalin was seen to have greater epiliptic potency than methionine-enkephalin. At doses of 1 microgram both enkephalins typically evoked cortical spindles resembling those seen in drowsy animals. Enkephalin-induced analgesia was seen in only one animal at the 100 microgram dose. Results obtained with repeated injections of morphine suggest that the epileptogenic effect of opiates may be subject to either tolerance or potentiation, depending on the prior occurrence of seizures. A synthesis of the present findings with several other lines of evidence suggests both that endogenous enkephalins play some role in normal mechanisms of reward, and that, when regulatory processes are disturbed, they may contribute as well to the elaboration of certain epileptic phenomena.

Topics: Animals; Dose-Response Relationship, Drug; Electroencephalography; Endorphins; Enkephalins; Injections, Intraventricular; Leucine; Male; Methionine; Morphine; Naloxone; Rats; Receptors, Opioid; Seizures

The endogenous opioid peptide, beta-endorphin, induces nonconvulsive limbic epileptiform activity when administered intraventricularly to rats. Epileptiform activity is elicited by beta-endorphin in doses that are devoid of analgesic or behavioral signs. Equimolar intraventricular doses of morphine or of the enkephalin analog [DAIa2,Met5]enkephalin-NH2 fail to elicit this limbic epileptiform activity. These observations, together with the recent immunohistochemical localization of beta-endorphin to midline limbic structures, suggest that beta-endorphin may have an important role in the regulation of limbic excitability.

Topics: Animals; Behavior, Animal; Electroencephalography; Endorphins; Enkephalins; Injections, Intraventricular; Limbic System; Morphine; Motor Activity; Naloxone; Rats; Seizures

From the following three lines of evidence, it is proposed that at least part of the convulsant activity of naloxone is a result of GABA receptor blockade. Firstly, iontophoretic naloxone reversibly antagonized GABA-evoked depression of firing rate in 21 of 27 neurons tested in the rat olfactory tubercle-nucleus accumbens region, without blocking inhibition evoked in the same cells by glycine (15 cells) or morphine (6 cells). Secondly, i.p. naloxone in high doses caused convulsions in mice, and potentiated the convulsant activity of bicuculline, but not that of strychnine. Diazepam, which protected mice against convulsions elicited by bicuculline, but not by strychnine, also protected mice against naloxone. Thirdly, naloxone, morphine, levorphanol and its non-analgesic enantiomer dextrorphan displaced 3H-GABA from GABA receptor sites in homogenates of human cerebellum, all with comparable low potencies (IC50 = 250--400 micron). There was no correlation with affinities at the stereospecific receptor sites that mediate opiate-induced analgesia, since the potent opiates etorphine and diprenorphine were relatively inactive (IC50 greater than 3 mM). In addition naloxone displaced 3H-GABA from receptor sites in rate forebrain and cerebellum, with similar low potency.

Topics: Action Potentials; Aminobutyrates; Animals; Binding, Competitive; Brain; GABA Antagonists; gamma-Aminobutyric Acid; Humans; In Vitro Techniques; Iontophoresis; Male; Mice; Naloxone; Rats; Receptors, Drug; Seizures

The administration of naloxone 2, 10, 50, or 250 mg/kg intravenously did not alter halothane requirement (MAC) in Sprague-Dawley rats (12 per group). Two rats convulsed when given 50 mg/kg while anesthetized with halothane. In a separate group of awake rats, seven of nine animals convulsed when given naloxone, 100 mg/kg. It is concluded that any effect of naloxone on anesthetic requirement must be small (not significant in our study), and that if an effect exists it is the result of a nonspecific analeptic action of naloxone rather than a specific action at opiate receptors.

Topics: Anesthesia, Inhalation; Animals; Dose-Response Relationship, Drug; Enkephalins; Halothane; Naloxone; Rats; Seizures; Spirometry

Topics: Animals; Behavior, Animal; Electroencephalography; Endorphins; Enkephalins; Female; Gerbillinae; Male; Naloxone; Seizures

The case of a 2 1/2-year-old comatose white boy successfully treated for acute phencyclidine poisoning has been reported with a brief review of symptoms and therapy. Supportive treatment consisted of maintaining intravascular volume; giving diuretics as needed to insure an adequate urinary output; controlling excessive secretions and seizure activity; and providing respiratory support. The patient recovered over a ten-day period of treatment without neurologic or psychologic sequelae.

Topics: Atropine; Child, Preschool; Diuretics; Humans; Kidney Function Tests; Liver Function Tests; Male; Naloxone; Phencyclidine; Respiration; Seizures

Systemic and intracerebroventricular administration of analgesic doses of morphine resulted in large increments of spontaneous multiple unit activity in the periaqueductal gray matter of the awake rat. Intracerebroventricular injection of methionine enkephalin gave analgesia in only 8 of 19 rats, but in all 8, and in no others, increased periaqueductal multiple unit firing was also seen. These findings support the view that the periaqueductal gray matter is actively involved in endogenous mechanisms of analgesia. A striking observation was that enkephalin caused electrographic and behavioral epileptic phenomena in most animals. This observation together with other recent findings suggests that endogenous enkephalin may play some role in epileptogenesis.

Topics: Action Potentials; Analgesia; Animals; Brain; Cerebral Aqueduct; Electroencephalography; Enkephalins; Injections, Intraventricular; Male; Morphine; Naloxone; Oligopeptides; Rats; Seizures

Topics: Amphetamine; Animals; Mice; Morphine; Naloxone; Pentylenetetrazole; Receptors, Opioid; Seizures; Substance P

Narcotic analgesics and related drugs act as agonists on several receptors that are responsible for their effects on pain perception, mood and feeling state, and respiration, as well as other pharmacologic actions. Naloxone is the first discovered antagonist that is devoid of agonistic activity and appears to be a competitive antagonist at several receptors. The ability of naloxone to displace or prevent the binding of agonistic narcotics is partly responsible for its antagonistic effects. The ability of naloxone to rectify narcotic-depressed homeostats and precipitate abstinence is also related to its antagonistic activity. Certain cautions and principles apply in the use of naloxone in treating narcotic overdose, reversing surgical analgesia, and the treatment of neonates and children. Unapproved uses of naloxine include reversing the psychotomimetic effects of certain agonists-antagonists, terminating narcotic-induced convulsions and coma, reversing non-narcotic depression, diagnosing physical dependence, and treating narcotic addicts.

Topics: Adult; Analgesics; Animals; Child; Coma; Female; Guinea Pigs; Humans; Infant, Newborn; Infant, Newborn, Diseases; Mice; Naloxone; Narcotic Antagonists; Narcotics; Pregnancy; Receptors, Opioid; Respiratory Distress Syndrome; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders

1 Morphine (1-200 mg/kg s.c.) reduced the incidence and prolonged the latency of priming-induced audiogenic siezures in a dose-dependent manner. 2 This effect was reversed by naloxone (1 and 2 mg/kg) although naloxone was itself inactive. 3 This priming-induces seizure model may be useful in the study of tolerance and physical dependence.

Topics: Acoustic Stimulation; Animals; Behavior, Animal; Depression, Chemical; Drug Interactions; Mice; Mice, Inbred BALB C; Morphine; Naloxone; Seizures

Naloxone antagonized convulsions produced by tail vein infusions of d-propoxyphene, heroin, meperidine, normeperidine and thebaine in mice in a dose-related manner. Pretreatment with naloxone (60 mg/kg i.p.) produced a 200 percent increase of the dose of d-propoxyphene or heroin needed to produce a seizure. A 40 percent increase in the convulsant dose of meperidine was observed after naloxone pretreatment (30 mg/kg i.p.). Naloxone (15 mg/kg i.p.) produced a 30 percent increase in the convulsant dose of normeperidine; however, larger doses of naloxone did not produce any further increase in the convulsant dose of either normeperidine or meperidine. Larger doses of naloxone were needed to antagonize convulsions produced by thebaine. Heroin, d-propoxyphene and meperidine produced nonlethal clonic seizures, whereas normeperidine and thebaine produced tonic-clonic seizures which were followed by death. These data suggest that there may be two mechanisms by which narcotic analgesics and their congeners produce convulsions.

Topics: Animals; Anticonvulsants; Dextropropoxyphene; Heroin; Male; Meperidine; Mice; Naloxone; Nipecotic Acids; Seizures; Thebaine

Topics: Adult; Dextropropoxyphene; Female; Humans; Ipecac; Naloxone; Poisoning; Respiratory Insufficiency; Seizures; Vomiting

Topics: Animals; Brain; Dose-Response Relationship, Drug; Drug Tolerance; Male; Mice; Morphine; Naloxone; Receptors, Opioid; Seizures; Stereoisomerism; Stereotyped Behavior

Topics: Acetylcholine; Animals; Behavior, Animal; Brain; Cats; Cerebral Cortex; Cerebral Ventricles; Heart; Humans; In Vitro Techniques; Injections, Intraperitoneal; Mollusca; Morphine; Morphine Dependence; Naloxone; Perfusion; Seizures; Substance Withdrawal Syndrome; Time Factors

Topics: Atropine; Drug Combinations; Gastrointestinal Agents; Humans; Infant; Ipecac; Isonipecotic Acids; Male; Naloxone; Poisoning; Respiration, Artificial; Seizures; Tachycardia; Vomiting

Topics: Animals; Binding Sites; Lysine; Male; Mice; Morphine; Naloxone; Peptides; Seizures

Topics: Analgesics; Animals; Codeine; Dextropropoxyphene; Dose-Response Relationship, Drug; Drug Interactions; Hot Temperature; Levorphanol; Male; Meperidine; Methadone; Mice; Mice, Inbred Strains; Naloxone; Pentazocine; Physical Stimulation; Reaction Time; Seizures; Time Factors; Tremor