Effect of linalool on morphine tolerance and dependence in mice

Phytother Res. 2012 Sep;26(9):1399-404. doi: 10.1002/ptr.3736. Epub 2012 Feb 8.


Linalool, a terpene alcohol, has been shown to interact with the opioid system and N-methyl-D-aspartate (NMDA) receptor. Therefore, the effect of linalool on morphine dependence and tolerance was studied. Dependence and tolerance were induced in mice using subcutaneous morphine injections, three times a day (50, 50 and 75 mg/kg /day) for 3 days. To evaluate the effect of agents on the induction of morphine dependence and tolerance, linalool (50, 75 and 100 mg/kg), clonidine (positive control), alpha-2 receptor agonist, (0.1 mg/kg), memantine, NMDA receptor antagonist (positive control), (30 mg/kg) and saline were injected intraperitoneally three times a day for 3 days. To determine the expression of morphine dependence and tolerance, all compounds were injected once intraperitoneally on the day of experiment. The effect of linalool and other agents on dependence were evaluated by counting the number of jumps (induced by naloxone 5 mg/kg). The tolerance was evaluated by the tail-flick test. The results showed that linalool in the induction and expression phase increased the nociception threshold. Linalool (48% and 95.6% at doses 75 and 100 mg/kg, respectively), clonidine and memantine reduced the severity of withdrawal signs in the induction and expression phases. This study indicated that linalool has a significant effect on morphine tolerance and dependence. This effect may be mediated partially through the inhibition of NMDA receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyclic Monoterpenes
  • Analgesics, Opioid / pharmacology
  • Animals
  • Clonidine / pharmacology
  • Drug Tolerance*
  • Male
  • Mice
  • Monoterpenes / pharmacology*
  • Morphine / pharmacology
  • Morphine Dependence / drug therapy*
  • Pain Measurement


  • Acyclic Monoterpenes
  • Analgesics, Opioid
  • Monoterpenes
  • Morphine
  • linalool
  • Clonidine