Blockade of orexin receptor 1 attenuates the development of morphine tolerance and physical dependence in rats

Pharmacol Biochem Behav. 2012 Dec;103(2):212-9. doi: 10.1016/j.pbb.2012.08.010. Epub 2012 Aug 27.


The goals of this study were to evaluate the effects of pretreatment by orexin receptor-1 antagonist on the development of morphine tolerance and physical dependence in rat. Animals were rendered dependent on morphine by subcutaneous (SC) injection of morphine sulfate (10mg/kg) at set intervals of 12h for 10days. Just before the morphine administration, the animals received SB-334867, a selective orexin receptor 1 (OXR1) antagonist. To assess morphine tolerance, the antinociceptive responses of morphine were measured using the warm-water tail immersion test before and after its administration. On day 11, naloxone was injected 2h after morphine administration and the physical dependence evaluated by quantifying/scoring naloxone-precipitated withdrawal signs for 30min. The effect of chronic SB-334867 on locomotion was carried out by calculating the number of grid crossings as a measure of locomotor activity. Our findings demonstrated that although morphine-tolerance tended to develop in response to repeated injections of morphine, pre-treatment of OXR1 antagonist prevented this effect, causing a delay in the development of morphine-tolerance. Moreover, co-administration of orexin receptor 1 antagonist with morphine significantly decreased the somatic signs of withdrawal including diarrhea, teeth chattering, jumping, and defecation. Administration of SB-334867 alone or in a chronic co-administration with morphine failed to change locomotor activity. These results suggest that the activation of OXR1 might be involved in the development of morphine tolerance and dependence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoxazoles / pharmacology
  • Drug Tolerance*
  • Male
  • Morphine / pharmacology*
  • Naphthyridines
  • Opioid-Related Disorders / physiopathology*
  • Orexin Receptors
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / physiology
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Receptors, Neuropeptide / physiology
  • Urea / analogs & derivatives
  • Urea / pharmacology


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