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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