title: The multiple PDZ domain protein Mpdz/MUPP1 regulates opioid tolerance and opioid-induced hyperalgesia.
abstract: BACKGROUND
  Opioids are a mainstay for the treatment of chronic pain. Unfortunately, therapy-limiting maladaptations such as loss of treatment effect (tolerance), and paradoxical opioid-induced hyperalgesia (OIH) can occur. The objective of this study was to identify genes responsible for opioid tolerance and OIH.
  
  
  RESULTS
  These studies used a well-established model of ascending morphine administration to induce tolerance, OIH and other opioid maladaptations in 23 strains of inbred mice. Genome-wide computational genetic mapping was then applied to the data in combination with a false discovery rate filter. Transgenic mice, gene expression experiments and immunoprecipitation assays were used to confirm the functional roles of the most strongly linked gene. The behavioral data processed using computational genetic mapping and false discovery rate filtering provided several strongly linked biologically plausible gene associations. The strongest of these was the highly polymorphic Mpdz gene coding for the post-synaptic scaffolding protein Mpdz/MUPP1. Heterozygous Mpdz +/- mice displayed reduced opioid tolerance and OIH. Mpdz gene expression and Mpdz/MUPP1 protein levels were lower in the spinal cords of low-adapting 129S1/Svlm mice than in high-adapting C57BL/6 mice. Morphine did not alter Mpdz expression levels. In addition, association of Mpdz/MUPP1 with its known binding partner CaMKII did not differ between these high- and low-adapting strains.
  
  
  CONCLUSIONS
  The degrees of maladaptive changes in response to repeated administration of morphine vary greatly across inbred strains of mice. Variants of the multiple PDZ domain gene Mpdz may contribute to the observed inter-strain variability in tolerance and OIH by virtue of changes in the level of their expression.
authors.affiliation: Department of Computer Science, Stanford University, Stanford, CA, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Donaldson
authors.affiliation: Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Anesthesiology, 112A, Palo Alto, CA, 94304, USA.|Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Anesthesiology, 112A, Palo Alto, CA, 94304, USA.|Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: De-Yong
authors.initials: DY
authors.lastname: Liang
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Anesthesiology, 112A, Palo Alto, CA, 94304, USA.|Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Peyman
authors.initials: P
authors.lastname: Sahbaie
authors.affiliation: Department of Computer Science, Stanford University, Stanford, CA, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Dill
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Peltz
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Kari J
authors.initials: KJ
authors.lastname: Buck
authors.affiliation: Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Anesthesiology, 112A, Palo Alto, CA, 94304, USA. djclark@stanford.edu.|Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA. djclark@stanford.edu.
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006239:Haplotypes; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009020:Morphine / Q000009:adverse effects*; D009021:Morphine Dependence / Q000235:genetics; D054731:PDZ Domains; D020641:Polymorphism, Single Nucleotide
chemical_list: D000701:Analgesics, Opioid; D002352:Carrier Proteins; D008565:Membrane Proteins; C491750:Mpdz protein, mouse; D009020:Morphine
keywords: Drug tolerance; Gene mapping; Opioid analgesics; Synaptic plasticity