Sleep and GABA levels in the oral part of rat pontine reticular formation are decreased by local and systemic administration of morphine

Watson, Christopher J.; Lydic, Ralph; Baghdoyan, Helen A.

doi:10.1016/j.neuroscience.2006.09.007

Cited by 59 publications

(52 citation statements)

References 68 publications

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“…In this way, reduction of the release of acetylcholine in the pontine GTF is one mechanism by which morphine inhibits REM sleep. In rats, morphine has been found to cause a concentrationdependent decrease in GABA levels of the oral part of the pontine reticular nucleus (PnO; Watson et al, 2007). Morphine may disrupt sleep by decreasing GABAergic transmission in the PnO.…”

Section: Introductionmentioning

confidence: 99%

Morphine Inhibits Sleep-Promoting Neurons in the Ventrolateral Preoptic Area Via Mu Receptors and Induces Wakefulness in Rats

Wang

Yue

et al. 2012

Neuropsychopharmacol

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Morphine is the most efficacious and widely prescribed treatment for pain. However, it decreases the total amount of deep sleep and rapid eye movement sleep in humans. Acute morphine administration at low doses causes wakefulness in animal models. To clarify the mechanism by which morphine affects sleep-wake behavior, we investigated the effects of morphine on the sleep-promoting neurons of the ventrolateral preoptic area (VLPO), a putative sleep-active nucleus, using in vitro brain slices by the patch-clamp technique. We also examined the effects of morphine on sleep-wake profiles after administration of opioid receptor antagonist to the VLPO using EEG and electromyogram recordings in freely moving rats. The results showed that morphine inhibited the firing rate of sleep-promoting neurons and hyperpolarized their membrane potentials without affecting interneurons in the VLPO. Morphine-induced hyperpolarization of membrane potentials could be reversed by, D-Phe-Cys-Thr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), a mu receptor antagonist, in the presence of tetrodotoxin. However, after the mu receptors were blocked by CTOP, morphine still suppressed the firing of the sleep-promoting neurons. This effect was antagonized by nor-BIN, a kappa receptor antagonist. Activation of kappa receptor by U50488H inhibited the firing of the sleep-promoting neurons. These results indicate that morphine could inhibit the activity of sleep-promoting neurons in the VLPO through mu and kappa receptors. EEG recordings revealed that morphine injected subcutaneously induced arousal in a dose-dependent manner. CTOP microinjected into VLPO antagonized the arousal effects of morphine, but nor-BIN did not. However, CTOP alone was not associated with any changes in the physiological sleep-wake cycle. Taken together, these findings clearly indicate that morphine inhibits sleep-promoting neurons in the VLPO by affecting mu receptors and so induces wakefulness in rats.

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Section: Introductionmentioning

confidence: 99%

Morphine Inhibits Sleep-Promoting Neurons in the Ventrolateral Preoptic Area Via Mu Receptors and Induces Wakefulness in Rats

Wang

Yue

et al. 2012

Neuropsychopharmacol

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“…In addition, Li and van den Pol 17) reported that the sedative effect induced by narcotics is attributable to an inhibition of the orexin arousal system via m receptors. On the other hand, Watson et al 18) found that an increase in wakefulness time induced by a low dose of morphine is produced through the decreasing GABAergic transmission; therefore, the wakefulness-promoting effect induced by a low dose of morphine may be due to an inhibition of the GABAergic system. In addition, it is known that morphine via opioid receptors exerts anxiolytic effects, probably by interacting with the dopaminergic system by suppressing GABA inhibitory input to dopamine neurons, thereby augmenting dopamine release.…”

Section: Discussionmentioning

confidence: 99%

Effects of Anti-dementia Drugs on Morphine-Induced Somnolence

Ishida

Suga

Akagi

et al. 2009

Biological & Pharmaceutical Bulletin

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It is well known that narcotics, such as morphine, fentanyl and oxycodone, have been used for patients with chronic pain. These narcotics cause several adverse effects; for example, somnolence, cognitive dysfunction, constipation and nausea. These adverse effects, especially somnolence, deteriorate the quality of life (QOL) of patients in the daytime.Morphine has high affinity for m, d and k receptors. On the other hand, it has been reported that opioid receptors were responsible for the sleep-wake cycle, [1][2][3][4] but there is little information about the effect of morphine on the sleepwake pattern; therefore, we tried to clarify the role of opioid receptors in the sleep-wake cycle by studying the characteristics of morphine in the sleep-wake pattern.Clinically, methylphenidate is used for the treatment of somnolence caused by opioid analgesics 5) ; however, drug dependence and tolerance were frequently observed during this drug therapy. On the other hand, it is recommended to use cholinesterase inhibitors for sedation or somnolence caused by narcotics in a clinical study 6) ; however, there is little evidence as to whether the above presumption is true or not. Donepezil is a centrally acting selective, competitive and reversible acetylcholinesterase inhibitor, widely used for the treatment of dementia. Moraes et al. 7) and we 8) reported that donepezil increased total times of wakefulness in human and animals, respectively. In addition, it has been reported that muscarinic and nicotinic acetylcholine receptors are responsible for the cognitive dysfunction caused by morphine in rats.9,10) N-Methyl-D-aspartic acid (NMDA) receptor antagonist, memantine, is also used for the treatment of dementia, which protects against neuronal death. From these findings, we presumed that anti-dementia drugs may be effective in not only cognitive dysfunction but also somnolence caused by narcotics.In the present study, therefore, we studied the characteristics of morphine in rat sleep patterns, and also the effects of donepezil and memantine on the somnolence caused by morphine in comparison with that of methylphenidate. MATERIALS AND METHODS AnimalsMale Wistar rats weighing 240-320 g (Japan SLC, Shizuoka) were used. All animals were maintained in an air-conditioned room with controlled temperature (24Ϯ2°C) and humidity (55Ϯ15%). They were housed in aluminum cages with sawdust and kept under a light-dark cycle (lights on from 07:00 to 19:00). The animals were allowed free access to food and water, except during the experiments. All procedures involving animals were conducted in accordance with the Guidelines for Animal Experiments at Okayama University Advanced Science Research Center.Surgery The animals were anesthetized with pentobarbital sodium (Nembutal 11) To record the electromyogram (EMG), stainless steel wire electrodes (200 mm) were implanted into the dorsal neck muscle. The electrodes were connected to a miniature receptacle and the whole assembly was fixed to the skull with dental cement. At least 7 d were allowed f...

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“…33 Opioids are the most widely used drugs for the treatment of pain, and negative side effects include disruption of the sleep-wake cycle. 57 GABA levels in the PnO are decreased by opioids 28 and increased by hypocretin-1. 13 Studies of GABA A -receptor point-mutated mice showing that systemic alterations of transmission at GABA A receptors can be antinociceptive 58 encourage continuing efforts to localize GABAergic modulation of nociception to specific brain regions.…”

Section: Disclosure Statementmentioning

confidence: 99%

“…13,28 Briefly, rats were anesthetized with isoflurane (Abbott Laboratories, North Chicago, IL) and implanted with 3 screw electrodes (8IE36320SPCE, Plastics One, Roanoke, VA) for recording the cortical electroencephalogram (EEG). Three pair of EEG electrodes were placed using the following stereotaxic coordinates relative to bregma: 1.0 mm anterior and 1.5 mm lateral, 2.0 mm posterior and 1.5 mm lateral, and 2.0 mm posterior and 1.27 mm lateral.…”

Section: Animals Surgery and Conditioning Of Behaviormentioning

confidence: 99%

“…29 Previously described methods were used for amplification, digitization, and fast Fourier transform (FFT) analysis of signals. 13,28 Briefly, FFT plots were constructed by analyzing EEG signals in 0.5-Hz increments every 2 seconds for frequencies ranging from 0.5 to 25.0 Hz. Five consecutive 2-second bins were averaged to produce 1 FFT for each 10-second epoch.…”

Section: Microinjections and Quantification Of Arousal Statesmentioning

confidence: 99%

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Hypocretin and GABA Interact in the Pontine Reticular Formation to Increase Wakefulness

Brevig

Watson²,

Lydic³

et al. 2010

Sleep

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underlies the pathophysiology of narcolepsy, 4,5 and disruption of hypocretin signaling in mouse, 6 rat, 7,8 and dog 9 leads to narcolepsy-cataplexy. Hypocretinergic neurons project to multiple areas of the brain, including those important for regulating sleep and wakefulness. 1 One such area is the pontine reticular nucleus, oral part (PnO). 1,10 The PnO is the rostral portion of the rodent pontine reticular formation 11 and contributes to the generation of wakefulness and rapid eye movement (REM) sleep. 12 Microinjection of hypocretin-1 into rat PnO causes an increase in wakefulness, 13 and microinjection of hypocretin-1 into cat pontine reticular formation increases the cortically activated states of REM sleep 14 or wakefulness. 15,16 Administering hypocretin-1 into the PnO may increase wakefulness by modulating the release of arousal-promoting neurotransmitters within the PnO. Direct administration of hypocretin-1 to the PnO of isoflurane-anesthetized rat causes a concentration-dependent increase in both acetylcholine (ACh) release 17 and GABA levels 13 within the PnO. Extracellular recording studies of PnO neurons in urethane-anesthetized rat show that iontophoretic application of hypocretin-1 causes a hyperpolarization that is blocked by prior application of bicuculline. 10 This finding indicates that the hypocretin-1-induced inhibition of PnO neurons is mediated by GABA A receptors. Identified GABAergic neurons in brainstem slices of mouse PnO have been shown to be excited by hypocretin-1, 18 and intracellular recording studies in halothane-anesthetized cat show that hypocretin-1 can also cause direct depolarization of PnO neurons and an increase in PnO neuronal firing rate. 14 Numerous studies have demonstrated that GABAergic transmission in the PnO increases wakefulness and inhibits REM sleep. 13,[19][20][21][22][23][24][25] The present study provides the first test of the hypothesis that the wakefulness-promoting effects of delivering hypocretin-1 into the PnO are mediated by GABA A receptors as well as by hypocretin receptors. This hypothesis was evaluated by determining whether (1) microinjection of hypocretin-1 into the PnO causes a concentration-dependent increase in wakefulness, (2) this increase in wakefulness is blocked by coadministration of the hypocretin receptor-1 (hcrt-r1) antagonist SB-334867, and (3) coadministration of the GABA A receptor antagonist bicuculline also blocks the wakefulness response to hypocretin-1. Portions of these data have been presented as abstracts. 26,27 MATERIALS AND METHODS Chemicals and Drug SolutionsHuman hypocretin-1 was purchased from California Peptide Research, Inc. (Napa, CA). Bicuculline methiodide was pur- Study Objectives: Hypocretin-1/orexin A administered directly into the oral part of rat pontine reticular formation (PnO) causes an increase in wakefulness and extracellular g-aminobutyric acid (GABA) levels. The receptors in the PnO that mediate these effects have not been identified. Therefore, this study tested the hypothesis that the increase in wa...

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Sleep and GABA levels in the oral part of rat pontine reticular formation are decreased by local and systemic administration of morphine

Cited by 59 publications

References 68 publications

Morphine Inhibits Sleep-Promoting Neurons in the Ventrolateral Preoptic Area Via Mu Receptors and Induces Wakefulness in Rats

Morphine Inhibits Sleep-Promoting Neurons in the Ventrolateral Preoptic Area Via Mu Receptors and Induces Wakefulness in Rats

Effects of Anti-dementia Drugs on Morphine-Induced Somnolence

Hypocretin and GABA Interact in the Pontine Reticular Formation to Increase Wakefulness

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