Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal

Dan Georgescu, Venetia Zachariou, Michel Barrot, Michihiro Mieda, Jon T. Willie, Amelia J Eisch, Masashi Yanagisawa, Eric J. Nestler, Ralph J. DiLeone

Research output: Contribution to journalArticlepeer-review

323 Scopus citations


The lateral hypothalamus (LH) is implicated in the behavioral actions of drugs of abuse, but the cellular and molecular basis of this role is unclear. Recent identification of neuropeptides localized in LH neurons has allowed for more specific studies of LH function. The LH-specific peptide orexin (hypocretin) has been shown to be important in arousal and sleep regulation. However, orexin cells of the LH project broadly throughout the brain such that orexin may influence other behaviors as well. In this study, we show that orexin neurons, and not nearby LH neurons expressing melanin-concentrating hormone (MCH), have μ-opioid receptors and respond to chronic morphine administration and opiate antagonist-precipitated morphine withdrawal. cAMP response element-mediated transcription is induced in a subset of orexin cells, but not MCH cells, after exposure to chronic morphine or induction of withdrawal. Additionally, c-Fos and the orexin gene itself are induced in orexin cells in the LH during morphine withdrawal. Finally, we show that orexin knock-out mice develop attenuated morphine dependence, as indicated by a less severe antagonist-precipitated withdrawal syndrome. Together, these studies support a role for the orexin system in molecular adaptations to morphine, and demonstrate dramatic differences in molecular responses among different populations of LH neurons.

Original languageEnglish (US)
Pages (from-to)3106-3111
Number of pages6
JournalJournal of Neuroscience
Issue number8
StatePublished - Apr 15 2003


  • CREB
  • Drug addiction
  • Melanin-concentrating hormone
  • Opiate withdrawal
  • c-Fos
  • μ-opioid receptor

ASJC Scopus subject areas

  • Neuroscience(all)


Dive into the research topics of 'Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal'. Together they form a unique fingerprint.

Cite this