Hexachlorophene-induced degeneration of adrenergic nerves: Application of quantitative image analysis to Falck-Hillarp fluorescence histochemistry

Summary Possible toxic effects of hexachlorophene (HCP) on sympathetic adrenergic nerves were studied using Falck-Hillarp fluorescence histochemistry on whole-mounts of albino rat irides. HCP dissolved in 5 l DMSO, or DMSO alone, was injected into the anterior chamber of the eye. HCP caused a dose-dependent degeneration of adrenergic nerves, first observable after 7 g and profound after 21 g. One and 3 days after 35 g of HCP there was an almost total loss of adrenergic nerves. Regeneration from remaining non-terminal axons led to an almost complete reformation of the adrenergic nerve plexus after 18 days. The results demonstrate a new aspect of hexachlorophene neurotoxicity, degeneration of peripheral adrenergic nerve terminals and suggest that neurotoxic actions on thin unmyelinated fiber systems should be looked for also in the central nervous system (CNS).Supported by the Swedish Council for Planning and Coordination of Research (project Chemical Hazards in the Environment), The Swedish Medical Research Council 14X-01305, 14P-5867, Magnus Bergvalls Stiftelse, and Karolinska Institutets Fonder     

Chlorhexidine-induced degeneration of adrenergic nerves

Summary Possible toxic effects of chlorhexidine (CHX) on the sympathetic adrenergic ground plexus were studied in whole mounts of albino rat irides using Falck-Hillarp fluorescence histochemistry. CHX dissolved in an isotone, buffered sodium-acetate solution or in 70% alcohol was injected into the anterior chamber of eye. CHX caused a marked and dose-dependent degeneration of adrenergic nerves. Two days after the lowest dose, 0,25 g (5 l of a 0.05% CHX solution), approximately 30% of the nerves had disappeared. Almost complete degeneration was observed after the same time with higher doses (2.5 g, 5.0 g, and 7.5 g corresponding to 0.5, 1.0, and 1.5% CHX respectively). Two weeks after the lowest dose, the nerves had regenerated almost completely. With the highest dose used, only some 40% of the normal adrenergic nerve plexus had reformed after 51 days. Alcohol as a solvent did not have an additive effect on the neurotoxic action caused by CHX. The results demonstrate yet another aspect of chlorhexidine neurotoxicity, degeneration of peripheral adrenergic nerve terminals. This suggests that neurotoxic actions on thin unmyelinated fiber systems should be looked for also in the central nervous system (CNS).Supported by the Swedisch Council for Planning and Coordination of Research (Project: Chemical Hazards in the Environment), The Swedish Medical Research Council (14X-03185; 14P-5867; 04P-6889), Magnus Bergvalls Stiftelse, and Karolinska Institute Fonder     

Licht- und elektronenmikroskopische sowie cytometrische Untersuchungen an peripheren Nerven beim Morbus Tangier

Summary A sural nerve biopsy was performed in a 55-year-old male patient with Tangier disease (familiallipoprotein deficiency). Light-microscopy showed an increase in the endoneural connective tissue and a loss of nerve fibers indicating a chronic peripheral neuropathy. Electron-microscopy revealed an accumulation of lipid droplets within Schwann cells of myelinated and unmyelinated nerve fibers. When compared with age-matched controls the myelinated fiber density was reduced with a relative preponderance of small myelinated fibers. In addition, distributional cytometric studies of nerve vibers in relation to the perineurium and endoneurial capillaries showed: Contrary to 4.6–7.5 m thick nerve fibers, which accumulated in the center of the nerve fascicle, small (0.5–4.5 m) and large (7.6–10.0 m) fibers lay nearby the perineurium. The measured increase in small myelinated nerve fibers around endoneurial capillaries may be explained as a sign of regeneration.

     

Effects of triiodothyronine on the normal and regenerating facial nerve of the rat

Summary The left facial nerve was crushed in 50 adult male rats. The animals were allocated to 5 groups: controls received daily subcutaneous injections of slightly alkaline water; experimental animals received triiodothyronine sodium (T3), 1.0 g per kg for 3, 7 or 28 days or 5.0 g per kg for 28 days. Functional recovery, due to axonal regeneration, was detected by observing the time required for return of the corneal reflex on the left side. Treatment with T3 did not significantly accelerate this recovery.The rats were killed on the 28th post-operative day. Axonal diameters and myelin sheath thicknesses were measured in transverse sections of the temporal branches of the facial nerves. Treatment with T3 (5.0 g per kg, 28 days) did not affect the diameters of axons in the unoperated nerves, but resulted in their myelin sheaths becoming thicker than in the controls. A positive correlation between the two parameters, absent in control animals, appeared after treatment with T3.In the regenerated nerves, the axonal diameters were smaller in T3-treated than in control animals, but the myelin thicknesses were greater. These changes were more pronounced in rats injected with T3 for 28 days than for shorter times. It is suggested that under the influence of exogenous T3, regenerating neurons synthesize axolemmal components more rapidly than axoplasmic material and that the hormone stimulates myelination of both normal and regenerating axons by an action upon the Schwann cells.     

Expression of transforming growth factor-β1 and interleukin-1β mRNA in rat brain following transient forebrain ischemia

Transforming growth factor-1 (TGF-1) and interleukin-1 mRNA expression were studied in rat brains after 30 min of global ischemia by in situ hybridization. Ischemia was produced by four-vessel occlusion followed by different recirculation times ranging between 15 min and 7 days. TGF-1 mRNA could first be detected 3 days after ischemia in the hippocampus, in layers II/III of cortex, in the striatum and in parts of the ventral thalamus. At 7 days after recirculation a prominent increase in TGF-1 mRNA was observed in the CA1 sector of the hippocampus. Induction of interleukin-1 mRNA, however, was less marked and limited to the rostral striatum 3 and 7 days after ischemia. TGF-1 expression 7 days after ischemia correlated well with the histological localization of regions where neuronal degeneration and subsequent astrocytic and microglial activation had occurred. In adjacent brain sections, the distribution of TGF-1 mRNA after 7 days closely resembled that of the immunostaining pattern of activated microglia, indicating that at this time point TGF-1 mRNA was mainly produced by microglial cells. The late induction of TGF-1 mRNA after ischemia points to an involvement in the persistent glial response rather than the initial glial activation. The differential pattern of interleukin-1 mRNA induction indicates regional variations of cytokine production after ischemic brain lesions.Supported in part by a grant from the European Charcot Foundation for Multiple Sclerosis Research (to J.G.)     

Dose response relationship between plasma ACTH and cortisol after the infusion of ACTH1–24

Summary The authors examined the dose response relationship between plasma ACTH and cortisol concentrations after the administration of various doses of ACTH_1–24 (0.025 g, 0.125 g, 0.25 g, 1 g, 250 g) in dexamethasone-suppressed normal volunteers. A logarithmic dose-response relationship between the dose of ACTH administered and plasma cortisol concentration was found. Although there was considerable variability in plasma ACTH concentrations, there was, however, a definite correlation between area under the curve for ACTH and area under the curve for cortisol after the various doses of ACTH.     

Morning administration of melatonin antagonizes the antigonadotrophic effect of afternoon injections of melatonin, 5-methoxytryptophol and arginine vasotocin in intact mice

Summary In intact prepubertal mice kept under a long photoperiod subcutaneous afternoon (4.30 p.m.) injections (20 g) but not morning (9.30 a.m.) injections (100 g) of melatonin and 5-methoxytryptophol elicited antigonadotrophic effects. A morning dose (100 g) of methoxytryptophol abolished the antigonadotrophic effects of afternoon injections of methoxytryptophol. Similarly the antigonadotrophic effects of afternoon injections of melatonin, 5-methoxytryptophol and arginine vasotocin could be partially destroyed by 100 g and completely abolished by 1 mg melatonin administered in the morning.     

Single drug therapy for intractable epilepsy

Summary Single drug therapy with either phenytoin or primidone resulted in complete seizure control in 11 of 35 patients (31%) referred to an epilepsy clinic for treatment of uncontrolled chronic epilepsy with complex-partial seizures. Complete seizure control was associated with an increase in the mean plasma concentrations from 14 g/ml to 23 g/ml phenytoin and from 34 g/ml to 40 g/ml phenobarbitone with no change in the antiepileptic drug. Insufficiently low plasma concentrations of less than 11 g/ml phenytoin or phenobarbitone were measured at the first visit in 14 patients (40%). Non-compliance was admitted by eight patients (23%). Optimum single drug therapy is of considerable clinical value in intractable epilepsy with complex-partial seizures.

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Zusammenfassung Eine Monotherapie mit Phenytoin oder Primidon führte zur Anfallsfreiheit bei 11 von 35 Patienten (31%), die wegen schwerbehandelbarer psychomotorischer Anfälle eine Epilepsieambulanz aufsuchten. Anfallsfreiheit trat auf bei einem Anstieg der mittleren Plasmakonzentration von 14 g/ml auf 23 g/ml Phenytoin und von 34 g/ml auf 40 g/ml Phenobarbital. Ein Wechsel der Medikamente war nicht notwendig. Während der ersten Untersuchung wurden bei 14 Patienten (40%) zu niedrige Plasmakonzentrationen von weniger als 11 g/ml Phenytoin oder Phenobarbital gefunden. 8 Patienten (23%) gaben eine unregelmäßige Einnahme der Medikamente (non-compliance) zu. Eine konsequente Monotherapie ist von klinischem Wert für die Behandlung von schwerbehandelbaren Epilepsien mit psychomotorischen Anfällen.

     

Involvement of norepinephrine neurons in the hypothermia induced by intracerebroventricular administration of 6-hydroxydopamine in mice,evidenced by antidepressants

Summary The intracerebroventricular (i.c.v.) administration of increasing doses of 6-hydroxydopamine (6OHDA) (12.5–50 g) induces in mice a dose-dependent hypothermic effect. This hypothermic effect is not affected either by serotonin uptake inhibitors (indalpine, clomipramine, trazodone, fluoxetine) or by dopamine uptake inhibitors (GBR 12783, amineptine). On the contrary, the hypothermia is partly antagonized by norepinephrine uptake inhibitors (desipramine, nomifensine, viloxazine, maprotiline, protryptiline), as well as amfonelic acid. The antagonism elicited by desipramine is observed when the drug is administered intraperitoneally (from 5 mg/kg) or intracerebroventricularly (from 5 g per mouse). 6-hydroxydopamine-induced hypothermia is antagonized by imipramine after a time lag of 1 hour; this antagonism lasts 6–11 hours after intraperitoneal administration of the drug (20 mg/kg). The hypothermic effect of 6-hydroxydopamine is diminished by a previous 6-hydroxydopamine i.c.v. administration (50 g, 7 days before), except in mice pretreated with desipramine at the time of the first 6-hydroxydopamine injection. The hypothermic effect is completely abolished by two previous 6-hydroxydopamine i.c.v. administrations (50 g, 7 days interval). It is also decreased in mice receiving DSP4 15 days before testing (50 mg/kg, i.p.). Finally, neither haloperidol (0.5 mg/kg i.p.) nor SCH 23390 (100 g/kg s.c.) antagonize 6-hydroxydopamine-induced hypothermia. It is concluded that this effect is largely depending on central norepinephrine neurons.     

Cytoplasmic and axoplasmic density variations in relation to hyperactivity

Summary The density of the cytoplasm and axoplasm of the anterior horn cell in rats was determined by X-ray microradiography. The average density of the cytoplasm of more than 400 cells from control rats was 0.31 g/³, while that of over 600 cells from rats fed IDPN (- iminodipropionitrile) was 0.43 g/³.Hyperactivity developed during the first 5 weeks and was associated with a gradual increase in cytoplasmic density to 0.51 g/³.At 6 weeks there was a drop in density to 0.36 g/³ which coincided with the appearance of axonal balloons having a density of 0.17 g/³.During the 7–12th week on the diet, the cytoplasmic density showed a gradual increase to 0.59 g/³ and the balloons to 0.29 g/³.The volume of the nerve cells remained fairly constant. The density increases were discussed in relation to hypertrophy, dystrophy, and hyperactivity.

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Zusammenfassung Die Dichte des Cytoplasmas und Axoplasmas der Vorderhornzellen von Ratten wurde durch Röntgenmikroradiographie bestimmt. Die mittlere Dichte des Cytoplasmas von mehr als 400 Zellen der Kontrollratten war 0,31 g/³, während die mittlere Dichte von mehr als 600 Zellen der Ratten, die mit IDPN (- iminodipropionitrile) gefüttert waren, 0,43 g/³ war.Hyperaktivität entwickelte sich während der ersten 5 Wochen und war mit einer progressiven Zunahme der Cytoplasmadichte bis auf 0,51 g/³ verbunden.Nach 6 Wochen sank die Dichte auf 0,36 g/³. Diese Tatsache traf mit dem Auftreten der Axonauftreibungen zusammen, die eine Dichte von 0,17 g/³ hatten.Nach 7–12 Wochen zeigte die Cytoplasmadichte eine progressive Zunahme auf 0,59 g/³ und die der Auftreibungen eine Zunahme auf 0,29 g/³.Das Volumen der Nervenzellen blieb ziemlich konstant.Die möglichen Zusammenhänge zwischen Zunahme der Dichte, Hypertrophie, Dystrophie und Hyperaktivität werden dargestellt.

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Supported by U. S. Public Health Grant NB 1305.     

The analysis of collagen in glutaraldehyde-fixed,osmicated peripheral nerve

Summary Glutaraldehyde fixation and osmication of rat sciatic nerve and human sural nerve did not appreciably alter the apparent weight of collagen in nerve fasciculi as determined by hydroxyproline analysis of hydrolysed samples. The collagen content of autopsied peripheral nerve is unaltered at least up to 24 h after death. The mean endoneurial weight of collagen per fascicle in rat sciatic nerve was 123 g (all results expressed for 1 cm length). In human sural nerve the mean weight was 57 g and the mean fascicular volume 1.74 mm³. Human endoneurial collagen fibrils gave a unimodal distribution of diameters with a peak at 40 nm.     

The concentrations of xanthine and hypoxanthine in cerebrospinal fluid as therapeutic guides in hydrocephalus

Xanthine, hypoxanthine, and total oxypurine levels were determined in the cerebrospinal fluid of 18 hydrocephalic patients and 8 healthy controls by high-performance liquid chromatography (HPLC). Eight of the hydrocephalic patients were self-compensated and 10 had shunts implanted during the course of the study. The mean xanthine, hypoxanthine, and total oxypurine levels in the normal children were 5.20, 5.94 and 11.29 mol/l, respectively. In self-compensated hydrocephalics these levels were respectively 6.06, 6.50 and 12.57 mol/l. In noncompensated hydrocephalics, they were 11.40, 10.79 and 22.19 mol/l. The differences between the latter group and the first two are statistically significant (P<0.001). Fifteen days after implantation of shunts in the noncompensated hydrocephalics, the mean xanthine levels had fallen to 4.61 mol/l, the mean hypoxanthine levels to 5.03 mol/l, and the mean total oxypurine levels to 9.64 mol/l. The change is statistically significant (P<0.001). In light of these findings we propose that xanthine, hypoxanthine, and total oxypurine levels be used in cases of hydrocephalus as guides for therapeutic action and to monitor progress.     

Effect of parasympathetic blockade on the signalaveraged electrocardiogram

Low parasympathetic activity is associated with late potentials detected at a noise level of 0.4 V in a signal-averaged electrocardiogram (SAECG) following myocardial infarction. In contrast, at a noise level of 0.2 V, lowering parasympathetic activity influences late potential parameters in the opposite direction in healthy subjects. The aim of this study was to estimate the relationship between parasympathetic activity and the SAECG obtained at noise levels of 0.4 and 0.2 V in healthy subjects. Two SAECG recordings in 10 healthy subjects were obtained at noise levels of 0.2 and 0.4 V before and after parasympathetic blockade using atropine (1 mg). Signal-averaged QRS duration (SA-QRS), late potential duration (LPD) defined as duration of terminal signals below 40 V, and root mean square voltage of the terminal 40 ms of the averaged QRS (RMS₄₀) were measured. At a noise level of 0.2 V SA-QRS reduced from 124±14 to 114±17 ms (P=0.008), LPD from 37±10 to 28±14 ms (P=0.01), and RMS₄₀ increased from 26±22 to 41±25 V (P=0.006) during parasympathetic blockade compared to baseline values. At a noise level of 0.4 V the SA-QRS (115±15 ms) and LPD (29±11 ms) were lower and the RMS₄₀ (37±23 V) was higher compared to the noise level 0.2 V, and no systematic alterations of the three variables were found during parasympathetic blockade. The parasympathetic nervous system may induce a very low-amplitude late potential in the SAECG. The data suggest that parasympathetic activity and a low noise level may lead to a false late potential-positive SAECG in low arrhythmia risk subjects. Therefore, we recommend the use of a noise level of 0.4 V or identification of high arrhythmia risk patients by late potentialand low parasympathetic activity.     

A special type of senile plaque,possibly an initial stage

Summary It is customary to distinguish primitive, classic and compact (burned out) senile plaques in Alzheimer's disease and senile dementia of the Alzheimer type (SDAT). Primitive plaques are characterized by altered neurites without accumulation of amyloid, classic plaques by an amyloid core surrounded by altered neurites and compact plaques by amyloid without pathological neurites. Here we describe a further type of plaque in which no amyloid or obviously altered neurites could be found by light microscopy with appropriate stains. This type of plaque was found mainly in the lateral entorhinal region and could be recognized by a slightly more intense staining and an altered texture of the neuropil in a spherical area having the same size as an early or mature plaque (100–150 m in diameter). In nonserial paraffin sections (3–4 m thick), a dark, silverpositive cell measuring 10–12 m in diameter was found in the center of 49 out of 400 such plaques (about 12%), which is the expected frequency if one assumes that every plaque contains such a cell and measures itself about 125 m. In fact, the reconstruction of 15 plaques (from four different patients) by means of serial sections demonstrated the presence of a central cell in each of them suggesting that this cell is an essential component of this plaque type. The central cell did not react with antibodies against cells of the mononuclear phagocyte lineage, such as alpha-1-antichymotrypsin, alpha-1-antitrypsin, leucocyte common antigen and lysozyme. However, it was consistently stained using the lectinRicinus communis agglutinin-1 (RCA-1), which is known to stain specifically microglia in the normal human brain. We assume that the type of plaque we describe might correspond to a very early step of plaque development and that they are possibly formed even before the primitive plaques mentioned above. We further suggest that such very early lesions might be caused by abnormal activity of microglial cells.     

Immunoglobulin heavy chain gene associations in myasthenia gravis: new evidence for disease heterogeneity

Summary Susceptibility to myasthenia gravis (MG) is known to involve genes residing in the major histocompatibility complex class I and II regions (HLA-B8 and DR3). Immunoglobulin heavy chain constant region (IgCH) allotypes have also shown some associations with MG. We have used restriction fragment length polymorphism analysis with probes to the IgCH switch (S) regions and 1 and the downstream marker D14S1 to investigate 189 Caucasoid patients with well-defined MG. A highly significant increase in the frequency of the 2.6 kilobase (kb) S homozygous genotype and the 2.6 kb S allele was found in patients with disease onset after the age of 40 years (late onset) compared with normal controls (P<0.00075 andP<0.025 respectively). No association was found at the S1 or D14S1 loci. In patients with an associated thymoma there was a moderate increase in the frequency of the 2.6 kb S and 7.4 kb S1 genotypes. These results independently support the previous separation of the late-onset subgroup. Finally, the stronger associations at S rather than at the downstream Sl, Gm and D14S1 loci suggest that the genes predisposing to MG are located within the variable region of the Ig heavy chain loci.     

Spheroids and altered axons in the spinal gray matter of the normal cat

Summary In our recent ultrastructural studies on synapses of the nucleus dorsalis, central cervical nucleus, and anterior horn of the spinal cord of the normal cat we happened to find spheroids and several types of axonal alterations. These spheroids were up to 39 m in diameter. They were found in myelinated and unmyelinated terminal axons and at the node of Ranvier and showed two different types of internal structure. One type was large and composed of spirally arranged neurofilaments and mitochondria in increased quantity, although the mean population density of mitochondria was not high being 1.4/m² as compared to the normal value 2.0/m². Another type was smaller and consisted of small mitochondria and dense bodies which were increased in number: their mean population densities were 4.5/m² and 1.9/m², respectively.At present, the rare occurrence of spheroids and atypical axonal alterations makes it difficult to determine the origin of affected axons, although some of them presumably arise from primary afferents.     

A study of the capacity of myelinated and unmyelinated nerves to induce experimental allergic neuritis

Summary The capacity of myelin-free Schwann cells to induce EAN was investigated. Human foetal peripheral nerve and human adult abdominal vagus nerve, both containing little or no myelin, failed to induce EAN when injected intradermally (together with Freund's adjuvant) into rabbits. In contrast, human adult sciatic nerve, which is heavily myelinated, induced characteristic signs and histopathology of EAN. Thus in the myelin-free antigens Schwann cell plasma membrane, from which myelin is apparently derived, failed to induce EAN. Reasons for this paradox are discussed.     

Concentrations of remoxipride and its phenolic metabolites in rat brain and plasma. Relationship to extrapyramidal side effects and atypical antipsychotic profile

Summary The cataleptic effect of remoxipride was examined in the horizontal bar test after i.v.,i.p. and s.c. administration to male rats. Remoxipride induced immediate catalepsy after high i.v. doses (ED₅₀=49 mol/kg) while peak effects were seen 60–90 min after i.p. administration (ED₅₀=38 mol/kg). Following s.c. administration remoxipride failed to produce a statistically significant catalepsy in the 20–100 mol/kg dose range (ED₅₀ > 100 mol/kg). In contrast, haloperidol was found to be more effective in inducing catalepsy after i.v. (ED₅₀=0.4 mol/kg) than after i.p. or s.c. administration (ED₅₀=0.9 mol/ kg). The atypical antipsychotic profile of remoxipride was more pronounced when the compound was given i.v. or s.c. as compared with the i.p. route. Plasma and brain (striatum and nucleus accumbens) concentrations of remoxipride and its active phenolic metabolites FLA 797(–) and FLA 908(–) were measured by high performance liquid chromatography. The 40 mol/kg dose of remoxipride resulted in plasma and brain concentrations of remoxipride which were 300–1000-fold higher (depending on the route of administration) than the most potent of the phenolic metabolites, e.g., FLA 797(–). The plasma and brain concentrations of remoxipride and its phenolic metabolites were related to DA D₂ receptor blocking potency and to the temporal course and effectiveness to induce catalepsy. This analysis suggested that the unbound concentrations of the phenolic metabolites were too low to play a major role in the DA blocking action of remoxipride. However, FLA 797(–) may contribute marginally to the cataleptic effects following high (i.p.) doses of remoxipride.     

Neurotoxic effects of aluminium on embryonic chick brain cultures

Toxic damage of brain cells by aluminium (A1) is discussed as a possible factor in the development of neurodegenerative disorders in humans. To investigate neurotoxic effects of A1, serum-free cultures of mechanically dissociated embryonic chick (stage 28–29) forebrain, brain stem and optic tectum, and for comparison meningeal cells, were treated with A1 (0–1000 M) for 7 days. Effects of A1 on cell viability (lysosomal and mitochondrial activity) and differentiation (synthesis of cell-specific proteins) were found to the brain area specific with the highest sensitivity observed in optic tectum. No inhibiting effects on cell viability could be observed in cultures of forebrain and meninges in the concentration range tested. In all three brain tissue cultures, threshold levels for the reduction of cell differentiation parameters were found at lower concentrations [concentration resulting in a 50% decrease (IC₅₀)>180 M] than for the inhibitionof cell viability (IC₅₀>280 M) indicating a specific toxic potential of A1 for cytoskeletal alterations. The culture levels of nerve cellspecific markers microtubule-associated protein type 2 (the most sensitive parameter) and the 68-kDa neurofilament were inhibited at lower concentrations (IC₅₀ 180–630 M) than the astrocyte-specific glial fibrillary acidic protein (IC₅₀ 700–1000 M), demonstrating a particularly high sensitivity of neurons in comparison to astrocytes. Based on these differences in A1 sensitivity observed for different cell markers in the various brain tissue cultures, the in vitro system used in the present study proved to be a suitable model to assess brain area and cell type-specific neurotoxic effects of A1.This study is part of the Ph. D. thesis of Judith P. Mueller.Preliminary results were presented at the 24th Annual Meeting of the Swiss Societies for Experimental Biology (USGEB/USSBE)     

Effects of chronic treatment with methadone and naltrexone on sleep in addicts

Previous studies have described sleep disturbance secondary to chronic opiate use and abuse. Drug-dependency insomnia is of interest because chronic sleep disturbances can promote depressive symptoms which could lead to a drug relapse. For the first time we compared the polysomnographic parameters of 10 methadone-substituted outpatients and 10 naltrexone-treated outpatients. Methadone (-opioid agonist) produced a marked fragmentation of the sleep architecture with frequent awakenings and a decrease in EEG arousals. In comparison with methadone and controls, the naltrexone (-opioid antagonist) group showed the shortest sleep latency and the longest total sleep time. These data indicate that -agonists and -antagonists have different effects on sleep. The implications, especially the involvement of opioid-dopamine interactions on sleep and movements during sleep, are discussed.