Antagonism of orexin type 1 receptors in the locus coeruleus attenuates signs of naloxone-precipitated morphine withdrawal in rats

Neurosci Lett. 2010 Oct 4;482(3):255-9. doi: 10.1016/j.neulet.2010.07.050. Epub 2010 Aug 2.


It has been shown that orexin neuropeptides contribute to morphine-induced physical dependence. The locus coeruleus (LC), which receives a dense extra-hypothalamic orexinergic projection, is a key brain region implicated in the expression of somatic signs of morphine withdrawal syndrome. The aim of the present study is to investigate the role of LC orexin type 1 receptors (OXR1) on naloxone-precipitated morphine withdrawal signs in rats. Adult male Wistar rats were rendered dependent on morphine by subcutaneous (s.c.) injection of morphine sulfate (10mg/kg) at an interval of 12h for 9 days. On day 10, naloxone (1mg/kg i.p.) was injected 2h after morphine administration. Somatic signs of withdrawal were then evaluated in a clear Plexiglas test chamber (30 cm diameter, 50 cm height) for 25 min. One group of animals received intra-LC SB-334867-A, a selective OXR1 antagonist, (100 microM, 0.2 microl) immediately before naloxone. In the control group, SB-334867-A vehicle was microinjected into the LC in the same manner. The results showed that intra-LC OXR1 receptor blockade significantly decreased the somatic signs of withdrawal including chewing, diarrhea, scratching, teeth chattering, wet-dog shake and ptosis. These results suggest that activation of OXR1 in the LC might be involved in the expression of withdrawal signs in morphine dependent rats.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoxazoles / administration & dosage
  • Injections, Intraventricular
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / metabolism*
  • Male
  • Morphine / adverse effects*
  • Morphine Dependence / metabolism
  • Naloxone / pharmacology
  • Naphthyridines
  • Narcotic Antagonists / pharmacology
  • Narcotics / adverse effects
  • Orexin Receptors
  • Rats
  • Rats, Wistar
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Neuropeptide / metabolism*
  • Substance Withdrawal Syndrome / metabolism*
  • Urea / administration & dosage
  • Urea / analogs & derivatives


  • 1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea
  • Benzoxazoles
  • Naphthyridines
  • Narcotic Antagonists
  • Narcotics
  • Orexin Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Naloxone
  • Morphine
  • Urea