Abstract
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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Acknowledgements
This study was supported in part by grants-in-aid for scientific research from the National Basic Research Program of China Grants (2009CB5220004 and 2011CB711000), National Natural Science Foundation of China (30970955, 30901797, 8100569, 31070957, 31171010, 31171049, 31121061, and 31271164), the Shanghai Committee of Science and Technology (10441901600 and 11ZR1402000), Shanghai Leading Academic Discipline Project (B119), PhD Programs Foundation of Ministry of Education of China (20110071110033), and China National Science and Technology Major Project for Drug Discovery (2009ZX09303-006).
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Wang, Q., Yue, XF., Qu, WM. et al. Morphine Inhibits Sleep-Promoting Neurons in the Ventrolateral Preoptic Area Via Mu Receptors and Induces Wakefulness in Rats. Neuropsychopharmacol 38, 791–801 (2013). https://doi.org/10.1038/npp.2012.244
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DOI: https://doi.org/10.1038/npp.2012.244
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