Modulation of extracellular signal-regulated kinase (ERK) by opioid and cannabinoid receptors that are expressed in the same cell

Brain Res. 2008 Jan 16;1189:23-32. doi: 10.1016/j.brainres.2007.10.070. Epub 2007 Nov 4.


In the present study we investigated the signal transduction pathways leading to the activation of extracellular signal-regulated kinase (ERK) by opioid or cannabinoid drugs, when their receptors are coexpressed in the same cell-type. In N18TG2 neuroblastoma cells, the opioid agonist etorphine and the cannabinoid agonist CP-55940 induced the phosphorylation of ERK by a similar mechanism that involved activation of delta-opioid receptors or CB1 cannabinoid receptors coupled to Gi/Go proteins, matrix metalloproteases, vascular endothelial growth factor (VEGF) receptors and MAPK/ERK kinase (MEK). In HEK-293 cells, these two drugs induced the phosphorylation of ERK by separate mechanisms. While CP-55940 activated ERK by transactivation of VEGFRs, similar to its effect in N18TG2 cells, the opioid agonist etorphine activated ERK by a mechanism that did not involve transactivation of a receptor tyrosine kinase. Interestingly, the activation of ERK by etorphine was resistant to the inhibition of MEK, suggesting the possible existence of a novel, undescribed yet mechanism for the activation of ERK by opioids. This mechanism was found to be specific to etorphine, as activation of ERK by the micro-opioid receptor (MOR) agonist DAMGO ([D-Ala(2), N-Me-Phe(4), Gly(5)-ol] enkephalin) was mediated by MEK in these cells, suggesting that etorphine and DAMGO activate distinct, ligand-specific, conformations of MOR. The characterization of cannabinoid- and opioid-induced ERK activation in these two cell-lines enables future studies into possible interactions between these two groups of drugs at the level of MAPK signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / pharmacology
  • Analgesics, Opioid / pharmacology
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Central Nervous System / cytology
  • Central Nervous System / metabolism*
  • Cyclohexanols / pharmacology
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Etorphine / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • MAP Kinase Kinase 1 / drug effects
  • MAP Kinase Kinase 1 / metabolism
  • Mice
  • Neuroblastoma
  • Neurons / drug effects
  • Neurons / metabolism*
  • Rats
  • Receptor, Cannabinoid, CB1 / drug effects
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptors, Cannabinoid / drug effects
  • Receptors, Cannabinoid / metabolism*
  • Receptors, G-Protein-Coupled / drug effects
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Opioid / drug effects
  • Receptors, Opioid / metabolism*
  • Receptors, Opioid, delta / drug effects
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, mu / drug effects
  • Receptors, Opioid, mu / metabolism
  • Vascular Endothelial Growth Factor Receptor-1 / drug effects
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism


  • Analgesics
  • Analgesics, Opioid
  • Cyclohexanols
  • Receptor, Cannabinoid, CB1
  • Receptors, Cannabinoid
  • Receptors, G-Protein-Coupled
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Etorphine
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • Vascular Endothelial Growth Factor Receptor-1
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 1
  • Map2k1 protein, mouse