QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, March 12, 2008, 28(11):2814-2819; doi:10.1523/JNEUROSCI.5447-07.2008

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Li, Y. Articles by van den Pol, A. N. Search for Related Content PubMed PubMed Citation Articles by Li, Y. Articles by van den Pol, A. N. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB MORPHINE

 Previous Article  |  Next Article 

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

Ying Li and Anthony N. van den Pol

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520

Correspondence should be addressed to Anthony N. van den Pol, Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520. Email: anthony.vandenpol{at}yale.edu

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-NH₂) and naloxone, antagonists of µ-opioid receptors, blocked µ agonist actions. In the absence of exogenous opioids, µ 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.

Key words: hypocretin; orexin; opiate; lateral hypothalamus; addiction; drug abuse

---

Received Dec. 10, 2007; revised Jan. 24, 2008; accepted Feb. 1, 2008.

Correspondence should be addressed to Anthony N. van den Pol, Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520. Email: anthony.vandenpol{at}yale.edu

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help