The Netrin-1 receptor DCC is a regulator of maladaptive responses to chronic morphine administration

Liang, De‐Yong; Zheng, Ming; Sun, Yuan; Sahbaie, Peyman; Low, Sarah; Peltz, Gary; Scherrer, Grégory; Flores, Cecilia; Clark, J. David

doi:10.1186/1471-2164-15-345

Cited by 22 publications

(21 citation statements)

References 56 publications

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“…To link our findings further to existing animal literature, we performed computational haplotype-based genetic mapping analyses 48 – 50 of data from 23 inbred mouse strains for a robust measure of opioid physical dependence, 48 counts of jumps made by morphine dependent mice after naloxone administration. Correlations were calculated for the distribution of the mean number of jumps per strain with known haplotype blocks across strains for CNIH3 and genes encoding AMPAR subunits and proteins involved in alterations of AMPAR subunit composition in response to opioids.…”

Section: Resultsmentioning

confidence: 99%

Evidence of CNIH3 involvement in opioid dependence

et al. 2015

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Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 SNPs, were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine, and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid dependent individuals. Meta-analyses found 5 genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective [p=4.30E-9; OR 0.64 (95%CI 0.55 – 0.74)]. Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP’s in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally-related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence complementing prior studies implicating the AMPA glutamate system.

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Section: Resultsmentioning

confidence: 99%

Evidence of CNIH3 involvement in opioid dependence

et al. 2015

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“…The analgesic effect of opioids might explain the positive association between chronic pain and opioid cessation. In addition, the Netrin-1 receptor gene, DCC, was related to chronic opioid exposure and chronic back pain in both mice and human studies [73,74].…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study of Opioid Cessation

Cox

Sherva

Lunetta

et al. 2020

JCM

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The United States is experiencing an epidemic of opioid use disorder (OUD) and overdose-related deaths. However, the genetic basis for the ability to discontinue opioid use has not been investigated. We performed a genome-wide association study (GWAS) of opioid cessation (defined as abstinence from illicit opioids for >1 year or <6 months before the interview date) in 1130 African American (AA) and 2919 European ancestry (EA) participants recruited for genetic studies of substance use disorders and who met lifetime Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for OUD. Association tests performed separately within each ethnic group were combined by meta-analysis with results obtained from the Comorbidity and Trauma Study. Although there were no genome-wide significant associations, we found suggestive associations with nine independent loci, including three which are biologically relevant: rs4740988 in PTPRD (pAA + EA = 2.24 × 10−6), rs36098404 in MYOM2 (pEA = 2.24 × 10−6), and rs592026 in SNAP25-AS1 (pEA = 6.53 × 10−6). Significant pathways identified in persons of European ancestry (EA) are related to vitamin D metabolism (p = 3.79 × 10−2) and fibroblast growth factor (FGF) signaling (p = 2.39 × 10−2). UK Biobank traits including smoking and drinking cessation and chronic back pain were significantly associated with opioid cessation using GWAS-derived polygenic risk scores. These results provide evidence for genetic influences on opioid cessation, suggest genetic overlap with other relevant traits, and may indicate potential novel therapeutic targets for OUD.

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“…1 Opioid-induced changes in nociceptive thresholds for 23 strains of mice. These data were reproduced from our earlier report [ 18 ]. In panel ( a ) the reduction in mechanical nociceptive thresholds are displayed as a fraction of the baseline thresholds.…”

Section: Resultsmentioning

confidence: 81%

“…Haplotype-based computational genetic mapping (HBCGM) has recently advanced to the point that whole-genome sequence data can be used to identify genetic factors affecting drug responses [ 17 ]. Using this approach, we recently found that the Dcc gene affects OIH and tolerance [ 18 ]. However, highly polymorphic genes have a relatively high probability for matching unrelated phenotypes by HBCGM due to the large number of haplotype blocks that can be formed within the gene.…”

Section: Introductionmentioning

confidence: 99%

The multiple PDZ domain protein Mpdz/MUPP1 regulates opioid tolerance and opioid-induced hyperalgesia

et al. 2016

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BackgroundOpioids 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.ResultsThese 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.ConclusionsThe 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.

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The Netrin-1 receptor DCC is a regulator of maladaptive responses to chronic morphine administration

Cited by 22 publications

References 56 publications

Evidence of CNIH3 involvement in opioid dependence

Evidence of CNIH3 involvement in opioid dependence

Genome-Wide Association Study of Opioid Cessation

The multiple PDZ domain protein Mpdz/MUPP1 regulates opioid tolerance and opioid-induced hyperalgesia

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