Potentiation of μ-opioid receptor-mediated signaling by ketamine

J Neurochem. 2011 Oct;119(2):294-302. doi: 10.1111/j.1471-4159.2011.07361.x. Epub 2011 Sep 20.


Ketamine, a clinically relevant drug, has been shown to enhance opioid-induced analgesia and prevent hyperalgesia. However, the molecular mechanisms involved are not clearly understood. As previous studies found that activation of opioid receptors leads to the phosphorylation of mitogen-activated protein kinases, we investigated whether ketamine could modulate μ-opioid receptor (μOR)-mediated ERK1/2 phosphorylation. We find that acute treatment with ketamine enhances (∼2- to 3-fold) the levels of opioid-induced ERK1/2 phosphorylation in recombinant as well as cells endogenously expressing μOR. Interestingly, we find that in the absence of ketamine ERK1/2 signaling is desensitized 10 min after opioid exposure whereas in its presence significant levels (∼3-fold over basal) are detected. In addition, ketamine increases the rate of resensitization of opioid-mediated ERK1/2 signaling (15 min in its presence vs. 30 min in its absence). These results suggest that ketamine increases the effectiveness of opiate-induced signaling by affecting multiple mechanisms. In addition, these effects are observed in heterologous cells expressing μOR suggesting a non-NMDA receptor-mediated action of ketamine. Together this could, in part, account for the observed effects of ketamine on the enhancement of the analgesic effects of opiates as well as in the duration of opiate-induced analgesia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CHO Cells
  • Cell Line, Tumor
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Humans
  • Ketamine / pharmacology*
  • Kinetics
  • Mitogen-Activated Protein Kinases / physiology
  • Neurons / drug effects
  • Phosphorylation
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / drug effects*
  • Signal Transduction / drug effects*


  • Excitatory Amino Acid Antagonists
  • Receptors, Opioid, mu
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Ketamine
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases