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Millions of Americans suffer from opiate use disorder, and over 100 die every day from opioid overdoses. Opioid use often progresses into a vicious cycle of abuse and withdrawal, resulting in very high rates of relapse. Although the physical and psychologic symptoms of opiate withdrawal are well-documented, sleep disturbances caused by chronic opioid exposure and withdrawal are less well-understood. These substances can significantly disrupt sleep acutely and in the long term. Yet poor sleep may influence opiate use, suggesting a bidirectional feed-forward interaction between poor sleep and opioid use. The neurobiology of how opioids affect sleep and how disrupted sleep affects opioid use is not well-understood. Here, we will summarize what is known about the effects of opioids on electroencephalographic sleep in humans and in animal models. We then discuss the neurobiology interface between reward-related brain regions that mediate arousal and wakefulness as well as the effect of opioids in sleep-related brain regions and neurotransmitter systems. Finally, we summarize what is known of the mechanisms underlying opioid exposure and sleep. A critical review of such studies, as well as recommendations of studies that evaluate the impact of manipulating sleep during withdrawal, will further our understanding of the cyclical feedback between sleep and opioid use. SIGNIFICANCE STATEMENT: We review recent studies on the mechanisms linking opioids and sleep. Opioids affect sleep, and sleep affects opioid use; however, the biology underlying this relationship is not understood. This review compiles recent studies in this area that fill this gap in knowledge.

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We hypothesize that sleep state-dependent withdrawal of serotonin (5-hydroxytryptamine, 5-HT) at upper airway (UAW) dilator motoneurons contributes significantly to sleep-related suppression of dilator muscle activity in obstructive sleep apnea. Identification of 5-HT receptor subtypes involved in postsynaptic facilitation of UAW motoneuron activity may provide pharmacotherapies for this prevalent disorder. We have adapted two assays to provide semi-quantitative measurements of mRNA copy numbers for 5-HT receptor subtypes in single UAW motoneurons. Specifically, soma of 111 hypoglossal (XII) motoneurons in 10 adult male rats were captured using a laser dissection microscope, and then used individually in single round molecular beacon polymerase chain reaction (PCR) for real-time quantitation of 5-HT(2A), 5-HT(2C), 5-HT(3), 5-HT(4), 5-HT(5A), 5-HT(5B), 5-HT(6) or 5-HT(7) receptor. Receptor mRNA copy numbers from single XII motoneurons were compared to control samples from within the XII nucleus and lateral medulla. All 20 motoneuronal soma assayed for the 5-HT(2A) receptor had measurable copy numbers (7028+/-2656 copies/cell). In contrast, copy numbers for the 5-HT(2A) receptor in XII non-motoneuronal (n=17) and lateral medulla (n=15) samples were 81+/-51 copies and 83+/-35 copies, respectively, P<0.05. Seven of 13 XII motoneurons assayed had measurable 5-HT(2C) receptor copy numbers of mRNA (287+/-112 copies/cell). XII soma had minimal 5-HT(3), 5-HT(4), 5-HT(5A), 5-HT(5B), 5-HT(6) or 5-HT(7) receptor mRNA. 5-HT(2A) receptor mRNA presence within XII motoneurons was confirmed with digoxigenin-labeled in situ hybridization. In summary, combined use of laser dissection and molecular beacon PCR revealed 5-HT(2A) receptor as the predominant 5-HT receptor mRNA in XII motoneurons, and identified small quantities of 5-HT(2C) receptor. This information will allow a more complete understanding of serotonergic control of respiratory activity.

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Obstructive sleep apnea is a prevalent disorder associated with significant neurobehavioral and cardiovascular morbidities. At present, however, there are no widely effective, well-tolerated pharmacotherapies for obstructive sleep apnea. The pathogenesis of this disorder predicts that sleep apnea should respond to drug therapies. Specifically, respiration during waking in persons with sleep apnea is normal, while collapse of the upper airway occurs exclusively in sleep. This state-dependency in upper airway patency suggests state-dependent changes in neurochemical control of the upper airway dilator motoneurons, and this, in turn, suggests that appropriate medications would maintain upper airway dilator function in sleep and prevent sleep related collapse of the upper airway. The past few years have brought significant insight into the neural mechanisms governing upper airway dilator muscle function. This article provides updates on neurochemical mechanisms, emphasizing a role for serotonergic control, and reviews recent drug therapy trials for sleep apnea. We are currently well poised to develop effective pharmacotherapies for obstructive sleep apnea, with opportunities to target several regions involved in respiratory control.

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Serotonin and serotoninergic drugs have significant effects on respiration, at many sites throughout the nervous system, and serotonin has been implicated in the pathogenesis of obstructive sleep apnea. Thus, understanding the serotoninergic mechanisms underlying respiratory control may help discover novel pharmacotherapies for sleep-disordered breathing. Ondansetron, a serotonin (5-HT) antagonist selective for the 5-HT3 receptor subtype has recently been shown to suppress sleep-related central apneas in rats, particularly in rapid-eye-movement (REM) sleep. To evaluate the potential of ondansetron in the treatment of obstructive sleep-disordered breathing, we have performed randomized trials of two doses of ondansetron (20 and 40 mg orally) and placebo (4 studies for each of the 3 conditions) in our animal model of obstructive sleep apnea, the English Bulldog. Ondansetron significantly reduced the respiratory disturbance index (RDI) in REM sleep from 24.15+/-4.85 events/hour at placebo to 11.01+/-1.56 events/hour with high dose treatment, n=4, p<0.05. In contrast, the effects of drug on the RDI in non-rapid-eye-movement (NREM) sleep (5.23+/-1.30 events/hour, placebo; 4.31+/-1.36, with 20 mg ondansetron and 2.89+/-1.30 with 40 mg ondansetron, n=4) were not significant. Ondansetron, however, had no effect on either sleep efficiency or sleep architecture, and there were no effects on either oxyhemoglobin saturation nadirs or on the sleep time with saturations <90%. Although a trend towards reduction in the latter measure of oxygenation was seen at the higher dose of ondansetron. These data suggest a therapeutic potential for ondansetron in obstructive sleep-disordered breathing, particularly REM sleep apnea.

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Systemically administered ondansetron, a 5-HT3 receptor antagonist, reduces obstructive sleep-disordered breathing (OSDB) events in the English bulldog. The neural mechanisms through which ondansetron acts are unknown. 5-HT3 receptor immunoreactivity and mRNA have been detected in the vicinity of upper airway dilator motoneurons (UAWDMn's), suggesting that this receptor may contribute to the state-dependent modulation of UADMn's. To characterize 5-HT3 receptor activity within a representative UAWD nucleus, we performed acute microinjections of selective 5-HT3 drugs, 1-(m-Chlorophenyl)-biguanide HCl, an agonist, and ondansetron, an antagonist, into a major population of UADMn's, the hypoglossal nucleus (XII), in anesthetized, paralyzed and mechanically-ventilated rats. The 5-HT3-selective drugs neither altered the baseline XII nerve activity nor the excitatory effect of 5-HT microinjected into the XII. In contrast, systemic-administration of ondansetron (3 mg/kg) produced a significant increase in the inspiratory modulation of XII nerve activity (to 195.8%+/-19.3 of control, p<0.001). Together, these data suggest that 5-HT3 receptors within the XII nucleus do not mediate 5-HT effects on XII motoneurons, rather antagonism of 5-HT3 receptors outside the XII nucleus can increase respiratory drive to XII motoneurons. These results highlight the importance of understanding serotonergic effects on respiratory drive outside the UAWD motor nuclei as we search for 5-HT drug therapies for OSDB.

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Significant differences in many aspects of sleep/wake activity among inbred strains of mice suggest genetic influences on the control of sleep. A number of genetic techniques, including transgenesis, random and targeted mutagenesis, and analysis of quantitative trait loci may be used to identify genetic loci. To take full advantage of these genetic approaches in mice, a comprehensive and robust description of behavioral states has been developed. An existing automated sleep scoring algorithm, designed for sleep analysis in rats, has been examined for acceptability in the analysis of baseline sleep structure and the response to sleep deprivation in mice. This algorithm was validated in three inbred strains (C57BL/6J, C3HeB/FeJ, 129X1/SvJ) and one hybrid line (C57BL/6J X C3HeB/FeJ). Overall accuracy rates for behavioral state detection (mean+/-SE) using this system in mice were: waking, 98.8%+/-0.4; NREM sleep, 97.1%+/-0.5; and REM sleep, 89.7%+/-1.4. Characterization of sleep has been extended to include measurements of sleep consolidation and fragmentation, REM sleep latency, and delta density decline with sleep. An experimental protocol is suggested for acquiring baseline sleep data for genetic studies. This sleep recording protocol, scoring, and analysis system is designed to facilitate the understanding of genetic basis of sleep structure.

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Obstructive sleep apnea hypopnea syndrome (OSAHS) is a prevalent disorder, for which there are no universally effective pharmacotherapeutics. We hypothesized that in OSAHS, excitatory serotoninergic influences are important for maintaining patency of the upper airway in waking, and that in sleep, reduced serotoninergic drive plays a significant role in upper airway collapse and OSAHS. The previously reported small responses in humans with OSAHS to serotoninergics may relate, in part, to study design and the drugs/doses selected. We therefore performed multitrials/dose, multidose, randomized sleep studies testing the effectiveness of a combination of serotoninergics, trazodone, and L-tryptophan, in our animal model of OSAHS, the English bulldog. Trazodone/L-tryptophan caused dose-dependent reductions in respiratory events in non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS). During NREMS, the respiratory disturbance index (RDI) +/- standard error was 6.3 +/- 1.4 events/h (placebo) and 0.9 +/- 0.3 (highest dose), p < 0.01. During REMS, the RDI was 31.4 +/- 6.1 events/h (placebo) and 11.5 +/- 4.3 (highest dose), p = 0.002. Trazodone/ L-tryptophan dose-dependently reduced sleep fragmentation, p = 0.03, increased sleep efficiency, p = 0.005, enhanced slow-wave sleep, p = 0.0004, and minimized sleep-related suppression of upper airway dilator activity, p < 0.02. Trazodone with L-tryptophan can treat sleep-disordered breathing (SDB) in an animal model of OSAHS; the effectiveness of this therapy may be related to increased upper airway dilator activity in sleep and/or enhanced slow-wave sleep.

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Dorsal mesopontine cholinergic neurons control rapid eye movement sleep (REMS) and wakefulness and contain nitric oxide (NO) synthase. To assess whether local inhibition of NO synthase has distinct effects on sleep, N-nitro-L-arginine methyl ester, an NO synthesis inhibitor (L-NAME, 80 mM), carbachol, a cholinergic agonist (2, 10 or 50 mM), or saline were microinjected (120-200 nl) into the dorsal mesopontine tegmentum in rats. Sleep-wake cycles were monitored during the subsequent 6 h periods. Compared to control injections, L-NAME changed the pattern of REMS by prolonging individual episodes with a small increase in the percentage time of REMS and no change in slow wave sleep (SWS). Carbachol, at 50 mM, enhanced wakefulness and suppressed both SWS and REMS, especially during the first 2 h post-injection. At the two lower concentrations, carbachol moderately enhanced REMS 2-6 h post-injection by increasing the frequency, rather than duration, of individual episodes. Thus, a reduced NO release in the dorsal pontine tegmentum has a powerful consolidating effect on REMS episodes, whereas the direction of the effect of carbachol on the amount of sleep, and REMS in particular, depends on the magnitude of cholinergic stimulation. The REMS-consolidating effects of NO synthase inhibition in the pons may result from modulatory effects of NO on the release of acetylcholine and other neurotransmitters within the dorsal mesopontine tegmentum.

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Serotonin has been hypothesized to play an important role in the central control of motor function. Consistent with this hypothesis, virtually all serotonergic neurons within the medullary nuclei raphe obscurus and raphe pallidus in cats are activated in response to specific motor challenges. To determine whether the response profile of serotonergic neurons in the midbrain is similar to that observed in the medulla, the single-unit activity of serotonergic dorsal raphe nucleus cells was studied during three specific motor activities: treadmill-induced locomotion, hypercarbia-induced ventilatory response and spontaneous feeding. In contrast to the results obtained for medullary raphe cells, none of the serotonergic dorsal raphe cells studied (n=26) demonstrated increased firing during treadmill-induced locomotion. A subset of serotonergic dorsal raphe cells (8/36) responded to the hypercarbic ventilatory challenge with increased firing rates that were directly related to the fraction of inspired carbon dioxide, and a non-overlapping subset of cells (6/31) was activated during feeding. All feeding-on cells demonstrated a rapid activation and de-activation coincident with feeding onset and offset, respectively. Although the proportions of serotonergic cells activated by hypercarbia or feeding in the dorsal raphe nucleus were similar to those found in the medullary raphe, there were several major distinctions in the response characteristics for the two cell groups. In contrast to the medullary serotonergic neurons, only a minority of dorsal raphe nucleus serotonergic neurons responded to a motor challenge. Overall, the above results suggest very different roles for the midbrain and medullary serotonergic neurons in response to motor activities.

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We reported previously that pharmacological blockade of somatodendritic 5-hydroxytryptamine (5-HT)1A autoreceptors with spiperone, a nonselective 5-HT1A antagonist, increases the spontaneous firing rate of central serotonergic neurons in awake cats. The present study examined the effects of systemic administration of two reportedly selective 5-HT1A receptor antagonists, (S)-WAY-100135 {N-tert-butyl-3-[4-(2-methoxyphenyl) piperazin-1-yl]-2-phenylpropanamide} and its more potent analog WAY-100635 {N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide}, on the single-unit activity of serotonergic neurons in the dorsal raphe nucleus of freely moving cats. In addition, we assessed the antagonist action of these compounds at the 5-HT1A autoreceptor by examining their ability to block the inhibition of serotonergic neuronal activity produced by systemic administration of 8-hydroxy-2-(di-n-propylamino)tetralin, a highly selective 5-HT1A agonist. Administration of (S)-WAY-100135 (0.025-1.0 mg/kg i.v.) moderately depressed neuronal activity at all doses tested. In contrast, administration of WAY-100635 (0.025-0.5 mg/kg i.v.) significantly increased neuronal activity. The stimulatory action of WAY-100635, like that of spiperone, was evident during wakefulness (when serotonergic neurons typically display a relatively high level of activity) but not during sleep (when serotonergic neurons display little or no spontaneous activity). Pretreatment with (S)-WAY-100135 (0.5 mg/kg i.v.) weakly attenuated the inhibitory action of 8-hydroxy-2-(di-n-propylamino)tetralin. In contrast, WAY-100635 at doses as low as 0.1 mg/kg i.v. completely blocked the action of 8-hydroxy-2-(di-n-propylamino)tetralin. The antagonist action of WAY-100635 at 5-HT1A autoreceptors closely paralleled its ability to increase neuronal activity. Overall, WAY-100635 appears to act as a selective 5-HT1A antagonist, whereas (S)-WAY-100135 does not. The results obtained with WAY-100635 confirm our previous findings obtained with spiperone and further support the hypothesis that 5-HT1A autoreceptor-mediated feedback inhibition operates under physiological conditions.

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Recent studies have shown excitatory effects of serotonin on upper airway motoneurons. This excitatory effect is normally present and arises from cells in the caudal raphe nuclei. The firing of these serotonergic neurons is reduced during sleep. To determine the importance of serotonin in the maintenance of patient airways and normal respiration in waking in obstructive sleep apnea, we studied the effects of two serotonin antagonists on upper airway dilator muscle activity, diaphragm activity, Sao2, and upper airway cross-sectional area in an animal model of sleep-disordered breathing, the English bulldog. Systemic administration of both antagonists resulted in significant reductions in the peak amplitudes of upper airway muscle respiratory bursts (range, 39 to 62% suppression; p < 0.05). Lesser reductions in diaphragm activity were noted (range, 10 to 33% suppression; p < 0.05). Oxyhemoglobin saturations also fell (p < 0.05), coinciding with suppressions in upper airway muscle activity. With reductions in dilator muscle activity, upper airway cross-sectional areas, as measured with cine CT, showed significant inspiratory collapse. These results support the hypothesis that serotonin is important in the maintenance of patent upper airways in obstructive sleep apnea.

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Serotonergic neuronal responses during three specific motor activities were studied in nuclei raphe obscurus (NRO) and raphe pallidus (NRP) of freely moving cats by means of extracellular single-unit recordings. Responses to treadmill-induced locomotion were primarily excitatory, with 21 of 24 neurons displaying increased firing rates, directly related to treadmill speed. Individual regression analyses determined three response patterns: maximal activation at low speed (0.25 m/sec), augmentation of neuronal activity only at high treadmill speed (0.77 m/sec), and a linear increase. A smaller fraction of NRO and NRP serotonergic neurons (6 of 27) also responded to hypercarbic ventilatory challenge with increased firing rates. The magnitude of neuronal response was dependent upon the fraction of inspired CO2 and was related to ventilatory motor output, specifically, inspiratory amplitude. A subgroup of neurons responsive to hypercarbia in wakefulness demonstrated significant reductions in neuronal response to hypercarbia in slow-wave sleep. Finally, unit activity for 12 of 29 cells increased in response to spontaneous feeding, displaying two distinct patterns of neuronal response in relation to onset and termination of feeding: rapid activation and deactivation versus a gradual increase and decrease. More than half of the cells studied under all three conditions were responsive to more than one motor task. These results indicate that serotonergic caudal raphe neurons are responsive to specific motor system challenges, with many neurons responsive to multiple motor tasks, and that the responsiveness of serotonergic neurons to at least one motor task, hypercarbic ventilatory challenge, is state dependent.

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Recently, investigators demonstrated that acute sleep deprivation in healthy subjects results in significant periodic decrements in ventilation during recovery rapid-eye-movement (REM) sleep. The neural bases of such phenomena are unknown. The decrements in ventilation coincide with REM sleep-associated phasic activities, such as bursts of eye movements. The purpose of this study was to determine the effects of acute sleep deprivation on control of diaphragm activity during recovery REM sleep. In chronically implanted, naturally sleeping, unrestrained cats, we recorded the electroencephalogram, electrooculogram, pontogeniculooccipital waves, neck and diaphragmatic electromyograms, and the computed moving average of the diaphragm. Acute sleep deprivation resulted in an increase in REM sleep-associated phasic alterations in diaphragmatic control during recovery REM sleep. There was an increase in the percentage of bursts during recovery REM sleep with reduced inspiratory drive. Acute sleep deprivation resulted in a substantial increase in the number of brief pauses (fractionations) in diaphragmatic activity during recovery REM sleep. Respiratory timing was also affected by sleep deprivation, with a reduced expiratory time resulting in an increased duty cycle ratio. There was a significant increase in the percentage of bursts with decremented peak amplitude of the moving average of the diaphragm, a measure that correlates with tidal volume. Despite significant increases in respiratory-related phasic alterations, there were no parallel increases in excitatory phenomena, i.e., eye movements or pontogeniculooccipital waves. These results imply that respiratory control mechanisms in REM sleep are sensitive to the effects of prior sleep deprivation.

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