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Arousal and maintenance of a wake state is dependent on the hypothalamic hypocretin/orexin system. We found that hypocretin neurons are depressed by opiates, drugs of abuse that reduce cognitive alertness. Met-enkephalin (mENK), an endogenous opioid, and exogenous opiates such as morphine inhibited the hypocretin system by direct actions on the cell body that include reduced spike frequency, hyperpolarization, increased G-protein-coupled inwardly rectifying K(+) channel current, and attenuated calcium current, and indirectly through reducing excitatory synaptic tone by a presynaptic mechanism. CTAP (H-d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH(2)) and naloxone, antagonists of mu-opioid receptors, blocked mu agonist actions. In the absence of exogenous opioids, mu receptor antagonists enhanced activity of the hypocretin system, suggesting ongoing inhibition by endogenous receptors. Morphine pretreatment attenuated subsequent excitatory responses to hypocretin, suggesting a long-lasting depression caused by opiate exposure. Chronic exposure to morphine reduced subsequent responses to morphine and to mENK, but increased the response to opioid receptor antagonists. Together, these data are consistent with the view that the hypocretin system may be an important direct target for drugs of abuse, including opiates, that induce sedation and mental lethargy.

μ-Opioid Receptor-Mediated Depression of the Hypothalamic Hypocretin/Orexin Arousal System