title: A6V polymorphism of the human μ-opioid receptor decreases signalling of morphine and endogenous opioids in vitro.
abstract: OBJECTIVE
  Polymorphisms of the μ opioid receptor (MOPr) may contribute to the variation in responses to opioid drugs in clinical and unregulated situations. The A6V variant of MOPr (MOPr-A6V) is present in up to 20% of individuals in some populations, and may be associated with heightened susceptibility to drug abuse. There are no functional studies examining the acute signalling of MOPr-A6V in vitro, so we investigated potential functional differences between MOPr and MOPr-A6V at several signalling pathways using structurally distinct opioid ligands.
  
  
  METHODS
  CHO and AtT-20 cells stably expressing MOPr and MOPr-A6V were used. AC inhibition and ERK1/2 phosphorylation were assayed in CHO cells; K channel activation was assayed in AtT-20 cells.
  
  
  RESULTS
  Buprenorphine did not inhibit AC or stimulate ERK1/2 phosphorylation in CHO cells expressing MOPr-A6V, but buprenorphine activation of K channels in AtT-20 cells was preserved. [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, morphine and β-endorphin inhibition of AC was significantly reduced via MOPr-A6V, as was signalling of all opioids to ERK1/2. However, there was little effect of the A6V variant on K channel activation.
  
  
  CONCLUSIONS
  Signalling to AC and ERK via the mutant MOPr-A6V was decreased for many opioids, including the clinically significant drugs morphine, buprenorphine and fentanyl, as well endogenous opioids. The MOPr-A6V variant is common and this compromised signalling may affect individual responses to opioid therapy, while the possible disruption of the endogenous opioid system may contribute to susceptibility to substance abuse.
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia.
authors.forename: Alisa
authors.initials: A
authors.lastname: Knapman
authors.forename: Marina
authors.initials: M
authors.lastname: Santiago
authors.forename: Mark
authors.initials: M
authors.lastname: Connor
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002047:Buprenorphine / Q000494:pharmacology; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005283:Fentanyl / Q000494:pharmacology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000819:agonists / Q000378:metabolism; D005838:Genotype; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D010641:Phenotype; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D001615:beta-Endorphin / Q000494:pharmacology
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000701:Analgesics, Opioid; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D002047:Buprenorphine; D001615:beta-Endorphin; D009020:Morphine; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000262:Adenylyl Cyclases; D005283:Fentanyl