Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Analgesics / pharmacology
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Analgesics, Opioid / pharmacology
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Animals
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Cell Line
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Cell Line, Tumor
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Central Nervous System / cytology
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Central Nervous System / metabolism*
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Cyclohexanols / pharmacology
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Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Etorphine / pharmacology
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Extracellular Signal-Regulated MAP Kinases / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Humans
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MAP Kinase Kinase 1 / drug effects
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MAP Kinase Kinase 1 / metabolism
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Mice
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Neuroblastoma
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Neurons / drug effects
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Neurons / metabolism*
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Rats
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Receptor, Cannabinoid, CB1 / drug effects
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Receptor, Cannabinoid, CB1 / metabolism
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Receptors, Cannabinoid / drug effects
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Receptors, Cannabinoid / metabolism*
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Receptors, G-Protein-Coupled / drug effects
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Receptors, G-Protein-Coupled / metabolism
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Receptors, Opioid / drug effects
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Receptors, Opioid / metabolism*
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Receptors, Opioid, delta / drug effects
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Receptors, Opioid, delta / metabolism
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Receptors, Opioid, mu / drug effects
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Receptors, Opioid, mu / metabolism
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Vascular Endothelial Growth Factor Receptor-1 / drug effects
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Vascular Endothelial Growth Factor Receptor-1 / metabolism
Substances
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Analgesics
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Analgesics, Opioid
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Cyclohexanols
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Receptor, Cannabinoid, CB1
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Receptors, Cannabinoid
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Receptors, G-Protein-Coupled
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Receptors, Opioid
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Receptors, Opioid, delta
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Receptors, Opioid, mu
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Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
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Etorphine
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3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
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Vascular Endothelial Growth Factor Receptor-1
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase 1
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Map2k1 protein, mouse