naloxone and Sleep-Wake-Disorders

The efficacy of each antidepressant available has been found equal to that of amitriptyline in double-blind studies. However, a few of them are being prescribed (at under-therapeutic doses) for sleep, in non-depressed persons, when there are relative contraindications for sedative-hypnotics. Following previous studies regarding the antinociceptive mechanisms of various antidepressants, we suggest that the involvement of the opioid system in some of the antidepressants' mechanism of action may contribute to these medications' use for the induction and maintenance of sleep. The mostly prescribed antidepressants for sleep are trazodone (a weak, but specific inhibitor of the synaptosomal uptake of serotonin, that also binds to alpha-1 and alpha-2 adrenoreceptor sites) and mirtazapine (a postsynaptic drug which enhances noradrenergic and 5-HT1A-mediated serotonergic neurotransmission via antagonism of central alpha-2-auto- and hetero-adrenoreceptors). In our previous studies when ICR mice were tested with a hotplate analgesia meter, both trazodone and mirtazapine induced, a naloxone-reversible antinociceptive effect following i.p administration. Summing up the various interactions of trazodone and mirtazapine with opioid, noradrenergic and serotonergic agonists and antagonists, we found that the antinociceptive effect of trazodone is influenced by the opioid receptor subtypes mu and delta (and a clear 5-HT mechanism of antinociception), while the antinociceptive effect of mirtazapine is mainly influenced by kappa and mu opioid receptor subtype (combined with both serotonergic and noradrenergic receptors). This opioid profile of the two drugs may be one of the explanations to their efficacy in the treatment of insomnia, when sedatives (either benzodiazepines or the non-benzodiazepine "Z-compounds") cannot be prescribed.

Topics: Analgesics; Analgesics, Opioid; Animals; Antidepressive Agents; Depression; Disease Models, Animal; Male; Mice; Mice, Inbred ICR; Mirtazapine; Naloxone; Receptors, Opioid; Serotonin; Sleep; Sleep Wake Disorders; Trazodone; Zolpidem

The positive effects of acupuncture at Feng-Chi acupoints on treating epilepsy and insomnia have been well-documented in ancient Chinese literature. However, there is a lack of scientific evidence to elucidate the underlying mechanisms behind these effects. Our previous study demonstrated that high-frequency (100 Hz) electroacupuncture (EA) at Feng-Chi acupoints deteriorates both pilocarpine-induced focal epilepsy and sleep disruptions. This study investigated the effects of low-frequency (10 Hz) EA on epileptic activities and epilepsy-induced sleep disruptions.. In rats, the Feng-Chi acupoint is located 3 mm away from the center of a line between the two ears. Rats received 30 min of 10 Hz EA stimuli per day before each day's dark period for three consecutive days. Our results indicated that administration of pilocarpine into the left CeA at the beginning of the dark period induced focal epilepsy and decreased both rapid eye movement (REM) sleep and non-REM (NREM) sleep during the consequent light period. Low-frequency (10 Hz) EA at Feng-Chi acupoints suppressed pilocarpine-induced epileptiform EEGs, and this effect was in turn blocked by naloxone (a broad-spectrum opioid receptor antagonist), but not by naloxonazine (a μ-receptor antagonist), naltrindole (a δ-receptor antagonist) and nor-binaltorphimine (a κ-receptor antagonist). Ten Hz EA enhanced NREM sleep during the dark period, and this enhancement was blocked by all of the opioid receptor antagonists. On the other hand, 10 Hz EA reversed pilocarpine-induced NREM suppression during the light period, and the EA's effect on the sleep disruption was only blocked by naloxonazine.. These results indicate that low-frequency EA stimulation of Feng-Chi acupoints is beneficial in improving epilepsy and epilepsy-induced sleep disruptions, and that opioid receptors in the CeA mediate EA's therapeutic effects.

Topics: Animals; Electroacupuncture; Electroencephalography; Epilepsies, Partial; Humans; Naloxone; Pilocarpine; Rats; Receptors, Opioid; Sleep Wake Disorders; Sleep, REM

An effective and safe treatment of insomnia in patients with neuropathic pain remains an unmet need. Melatonin and its analogs have been shown to have both analgesic and hypnotic effects; however, capacity of them on sleep disturbance with neuropathic pain as well as the precise mechanism is unclear.. The present study evaluated effects of piromelatine, a novel melatonin receptor agonist, on sleep disturbance in a neuropathic pain-like condition as well as the underlying mechanisms.. A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSL) was employed. The antinociceptive and hypnotic effects of piromelatine were evaluated by measurement of thermal hyperalgesia, mechanical allodynia, and electroencephalogram (EEG) recordings in PSL mice. Pharmacological approaches were used to clarify the mechanisms of action of piromelatine.. PSL significantly lowered thermal and mechanical latencies and decreased non-rapid eye movement (NREM) sleep, and PSL mice exhibited sleep fragmentation. Treatment with 25, 50, or 100 mg/kg of piromelatine significantly prolonged thermal and mechanical latencies and increased NREM sleep. Moreover, the antinociceptive effect of piromelatine was prevented by melatonin antagonist luzindole, opioid receptor antagonist naloxone, or 5HT1A receptor antagonist WAY-100635. The hypnotic effect of piromelatine was blocked by luzindole but neither by naloxone nor WAY-100635.. These data indicate that piromelatine is an effective treatment for both neuropathic pain and sleep disturbance in PSL mice. The antinociceptive effect of piromelatine is likely mediated by melatonin, opioid, and 5HT1A receptors; however, the hypnotic effect of piromelatine appears to be mediated by melatonin receptors.

Topics: Analgesics; Animals; Disease Models, Animal; Hyperalgesia; Hypnotics and Sedatives; Indoles; Male; Melatonin; Mice; Naloxone; Narcotic Antagonists; Neuralgia; Pain Measurement; Peripheral Nerve Injuries; Piperazines; Pyrans; Pyridines; Receptor, Serotonin, 5-HT1A; Receptors, Melatonin; Receptors, Opioid; Sciatic Nerve; Serotonin Antagonists; Sleep Wake Disorders; Tryptamines

A simple blind study with small doses of naloxone (0.8-1.6 mg i.v.) was carried out in 11 patients with hypersomnia with sleep apnoea (HSA). The effect was studied by diurnal polysomnography. It was found that the administration of naloxone was followed by significant prolongation of wakefulness and by significant shortening of the total duration of the second stage of NREM sleep. The duration of the apnoeic episodes was also significantly shortened after naloxone, although their number did not alter. Increased activity of the endorphinergic system (which naloxone inhibits by receptor competition) evidently plays a role in the pathophysiology of HSA.

Topics: Adult; Disorders of Excessive Somnolence; Female; Humans; Male; Middle Aged; Naloxone; Single-Blind Method; Sleep Apnea Syndromes; Sleep Wake Disorders; Sleep, REM

The restless legs syndrome is a sensory and motor disorder of evening, repose, and sleep. The cardinal features include (a) restlessness, which is frequently associated with (b) dysesthesias, (c) myoclonic jerks and other dyskinesias while awake, (d) periodic movements of sleep, and (e) sleep disturbances. We have recently had the opportunity to study two patients severely affected by this syndrome whose family histories are consistent with dominant inheritance. Both patients serendipitously discovered that their symptoms responded uniquely well to opiate medication. Both patients were studied extensively with electrophysiological and videotape monitoring, and their movements were characterized. In both patients, all elements of the syndrome responded to opiates, with marked relief of symptoms and without any significant side effects. The specific opiate antagonist naloxone blocked the therapeutic benefit of the opiates. Our findings support the involvement of the endogenous opiate system in the pathogenesis of restless legs and related dyskinesias and suggest that opiate therapy may be a potentially valuable treatment for this sometimes disabling syndrome.

Topics: Aged; Dextropropoxyphene; Electrocardiography; Electroencephalography; Electrooculography; Endorphins; Female; Humans; Male; Methadone; Middle Aged; Myoclonus; Naloxone; Narcotics; Restless Legs Syndrome; Sleep Wake Disorders