The multiple PDZ domain protein Mpdz/MUPP1 regulates opioid tolerance and opioid-induced hyperalgesia. (December 2016)

• Record Type: Journal Article
• Authors: Donaldson, Robin; Sun, Yuan; Liang, De-Yong; Zheng, Ming; Sahbaie, Peyman; Dill, David; Peltz, Gary; Buck, Kari; Clark, J.
• Is Part Of: BMC genomics. Volume 17:Number 1(2016)
• Page Start: 1
• Page End: 12
• Publication Date: 2016-12
• Subjects: Opioid analgesics -- Drug tolerance -- Gene mapping -- Synaptic plasticity; Genomes -- Periodicals; Gene mapping -- Periodicals; Genomics -- Periodicals; Base Sequence -- Periodicals; Chromosome Mapping -- Periodicals; Genetic Techniques -- Periodicals; Sequence Analysis, DNA -- Periodicals; 572.8605
• DOI: 10.1186/s12864-016-2634-1
• Languages: English
• ISSNs: 1471-2164

Abstract

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 polymorphicMpdz gene coding for the post-synaptic scaffolding protein Mpdz/MUPP1. HeterozygousMpdz +/− 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 alterMpdz 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 geneMpdz may contribute to the observed inter-strain variability in tolerance and OIH by virtue of changes in the level of their expression.