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Opioid-induced hyperalgesia in 23 strains of inbred mice. For each strain, mice were tested for mechanical nociceptive thresholds at baseline and after 4 days of morphine treatment. Nociceptive thresholds after morphine treatment were divided by baseline values to obtain the fraction of baseline values. For each strain n = 8 mice. Mean values are displayed +/- S.E.M.
Source publication
Background
Opioids are the cornerstone of treatment for moderate to severe pain, but chronic use leads to maladaptations that include: tolerance, dependence and opioid-induced hyperalgesia (OIH). These responses limit the utility of opioids, as well as our ability to control chronic pain. Despite decades of research, we have no therapies or proven...
Contexts in source publication
Context 1
... of this data were used in previous mapping efforts [8,13,14]. The behavior response of principal interest in these studies was OIH; a mechanical stimulus was used to characterize changes in nocicep- tive thresholds at baseline and after chronic morphine treatment ( Figure 1). The percent reduction of mechan- ical nociceptive thresholds after chronic opioid treat- ment varied approximately 7-fold across the 23 strains analyzed. ...
Context 2
... note, there was not a significant correlation between baseline mechanical threshold and the degree of OIH observed after chronic morphine treatment (P > 0.05). Additional file 1: Figure S1 provides data for other chronic opioid adaptive traits analyzed here, including: hindpaw OIH measured using Hargreave's thermal test- ing, OIH measured using tail-flick thermal testing, anal- gesic tolerance and physical dependence. ...
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Citations
... Some of these earlier findings reported significant differences in the behavioral response to morphine and heroin, with BL6 mice demonstrating robust locomotor sensitization and rewardrelated behaviors that were absent or diminished in 129 mice (Dockstader and van der Kooy 2001;Murphy et al. 2001;Szumlinski et al. 2005). More recent haplotype-based computational genetic mapping across multiple inbred strains, including BL6 and 129 strains, have identified candidate genes associated with phenotypic variation in opioid sensitivity and adaptations (Donaldson et al. 2016;Liang et al. 2014). These data replicate previous findings showing attenuated naloxone-precipitated withdrawal in the 129 strain as compared to the BL6 strain (Donaldson et al. 2016;Kest et al. 2002aKest et al. , 2002bLiang et al. 2014). ...
... More recent haplotype-based computational genetic mapping across multiple inbred strains, including BL6 and 129 strains, have identified candidate genes associated with phenotypic variation in opioid sensitivity and adaptations (Donaldson et al. 2016;Liang et al. 2014). These data replicate previous findings showing attenuated naloxone-precipitated withdrawal in the 129 strain as compared to the BL6 strain (Donaldson et al. 2016;Kest et al. 2002aKest et al. , 2002bLiang et al. 2014). ...
Rationale
Transgenerational effects of preconception morphine exposure in female rats have been reported which suggest that epigenetic modifications triggered by female opioid exposure, even when that exposure ends several weeks prior to pregnancy, has significant ramifications for their future offspring.
Objective
The current study compares two mouse strains with well-established genetic variation in their response to mu opioid receptor agonists, C57BL/6J (BL6) and 129S1/svlmJ (129) to determine whether genetic background modifies the impact of preconception opioid exposure.
Methods
Adolescent females from both strains were injected daily with morphine for a total of 10 days using an increasing dosing regimen with controls receiving saline. Several weeks after their final injection, aged-matched BL6 and 129 morphine (Mor-F0) or saline (Sal-F0) females were mated with drug naïve males to generate Mor-F1 and Sal-F1 offspring, respectively. As adults, F1 mice were made morphine dependent using thrice daily morphine injections for 4 days. On day 5, mice were administered either saline or morphine followed 3 h later by naloxone. Behavioral and physiological signs of withdrawal were then measured.
Results
Regardless of strain or sex, morphine-dependent Mor-F1 mice had significantly lower levels of withdrawal-induced corticosterone but significantly higher glucose levels when compared to Sal-F1 controls. In contrast, both strain- and preconception opioid exposure effects on physical signs of morphine dependence were observed.
... The Netrin-1 receptor DCC has been demonstrated to be involved in physical dependence and tolerance to morphine (Liang et al. 2014). Furthermore, Dcc haploinsufficiency is associated with alterations in the incentive properties of amphetamine and methamphetamine (Grant et al. 2007;Kim et al. 2013). ...
... It is interesting to note that Dcc haploinsufficiency has been linked to maladaptive responses to chronic morphine administration (Liang et al., 2014). Using whole-genome sequence data from different mice strains, the authors identified that the allelic pattern within the Dcc gene is robustly associated with opioid-induced hyperalgesia, tolerance, and dependence after chronic opioid exposure (Liang et al. 2014). ...
... It is interesting to note that Dcc haploinsufficiency has been linked to maladaptive responses to chronic morphine administration (Liang et al., 2014). Using whole-genome sequence data from different mice strains, the authors identified that the allelic pattern within the Dcc gene is robustly associated with opioid-induced hyperalgesia, tolerance, and dependence after chronic opioid exposure (Liang et al. 2014). Dcc haploinsufficient mice were found to be impervious to the development of these maladaptations as they showed decrease tolerance, dependence, and opioidinduced hyperalgesia (Liang et al. 2014). ...
Rationale
The Netrin-1/DCC guidance cue pathway is critically involved in the adolescent organization of the mesocorticolimbic dopamine circuitry. Adult mice heterozygous for Dcc show reduced dopamine release in the nucleus accumbens in response to amphetamine and, in turn, blunted sensitivity to the rewarding effects of this drug.
Objective
Here, we tested whether the protective effects of Dcc haploinsufficiency are specific to stimulant drugs of abuse or instead extrapolate to opioids and ethanol.
Methods
We used the place preference paradigm to measure the rewarding effects of cocaine (20 mg/kg), morphine (5 or 10 mg/Kg), or ethanol (20%) in adult (PND 75) male Dcc haploinsufficient mice or their wild-type litter mates. In a second experiment, we compared in these two genotypes, in vivo dopamine release in the nucleus accumbens after a single i.p. injection of morphine (10 mg/kg).
Results
We found reduced morphine-induced dopamine release in the nucleus accumbens of Dcc haploinsufficient male mice, but, contrary to the effects of stimulant drugs, there is no effect of genotype on morphine-induced conditioned preference.
Conclusion
These findings show that reduced drug-induced mesolimbic dopamine in Dcc haploinsufficient male mice protects specifically against the rewarding effects of stimulant drugs, but not against the rewarding properties of morphine and ethanol. These results suggest that these drugs exert their rewarding effect via different brain circuits.
... Western blottings showed that Dcc protein levels are reduced by ;50% in Dcc 1/À embryonic spinal cords compared with WT spinal cords (n = 6 embryos per genotype, Mann-Whitney test, p = 0.002; Fig. 8). This is consistent with what has been observed previously in adult Dcc 1/À mouse spinal cords (Liang et al., 2014). ...
Axon guidance receptors such as DCC contribute to the normal formation of neural circuits, and their mutations can be associated with neural defects. In humans, heterozygous mutations in DCC have been linked to congenital mirror movements, which are involuntary movements on one side of the body that mirror voluntary movements of the opposite side. In mice, obvious hopping phenotypes have been reported for bi-allelic Dcc mutations, while heterozygous mutants have not been closely examined. We hypothesized that a detailed characterization of Dcc heterozygous mice may reveal impaired corticospinal and spinal functions. Anterograde tracing of the Dcc+/- motor cortex revealed a normally projecting corticospinal tract, intracortical microstimulation evoked normal contralateral motor responses, and behavioral tests showed normal skilled forelimb coordination. Gait analyses also showed a normal locomotor pattern and rhythm in adult Dcc+/- mice during treadmill locomotion, except for a decreased occurrence of out-of-phase walk and an increased duty cycle of the stance phase at slow walking speed. Neonatal isolated Dcc+/- spinal cords had normal left-right and flexor-extensor coupling, along with normal locomotor pattern and rhythm, except for an increase in the flexor-related motoneuronal output. Although Dcc+/- mice do not exhibit any obvious bilateral impairments like those in humans, they exhibit subtle motor deficits during neonatal and adult locomotion.SIGNIFICANCE STATEMENTWe show that loss of one Dcc allele does not affect motor cortex, corticospinal efficacy, or skilled locomotor control in adult mice, but it increases flexor-related motoneuronal output in the developing spinal cord and increases duty cycle of the stance phase during treadmill locomotion at slow walking speeds in adult mice. This finding raises the possibility of the existence of subtle locomotor changes in humans carrying monoallelic DCC mutations.
... Then, genetic factors are computationally predicted by identifying genomic regions (haplotype blocks) where the pattern of within-block genetic variation correlates with the distribution of phenotypic responses among the strains (Liao et al., 2004;Wang and Peltz, 2005;Zheng et al., 2012). HBCGM has successfully identified genetic factors for >22 biomedical traits in mice (Grupe et al., 2001;Rozzo et al., 2001;Liao et al., 2004;Guo et al., 2006Guo et al., , 2007Liang et al., 2006;Smith et al., 2008;Zaas et al., 2008;Chu et al., 2009;LaCroix-Fralish et al., 2009;Hu et al., 2010a,b;Liu et al., 2010Liu et al., , 2012Tregoning et al., 2010;Peltz et al., 2011;Sorge et al., 2012;Zheng et al., 2012Zheng et al., , 2015Zhang et al., 2016;Liang et al., 2014;Donaldson et al., 2016;Ren et al., 2020). However, as with other GWAS methods, HBCGM analyses identify many genomic regions with allelic patterns that correlate with a phenotypic response pattern; but only a few contain a causative genetic factor . ...
The ability to use genome-wide association studies (GWAS) for genetic discovery depends upon our ability to distinguish true causative from false positive association signals. Population structure (PS) has been shown to cause false positive signals in GWAS. PS correction is routinely used for analysis of human GWAS results, and it has been assumed that it also should be utilized for murine GWAS using inbred strains. Nevertheless, there are fundamental differences between murine and human GWAS, and the impact of PS on murine GWAS results has not been carefully investigated. To assess the impact of PS on murine GWAS, we examined 8223 datasets that characterized biomedical responses in panels of inbred mouse strains. Rather than treat PS as a confounding variable, we examined it as a response variable. Surprisingly, we found that PS had a minimal impact on datasets measuring responses in ≤20 strains; and had surprisingly little impact on most datasets characterizing 21 – 40 inbred strains. Moreover, we show that true positive association signals arising from haplotype blocks, SNPs or indels, which were experimentally demonstrated to be causative for trait differences, would be rejected if PS correction were applied to them. Our results indicate because of the special conditions created by GWAS (the use of inbred strains, small sample sizes) PS assessment results should be carefully evaluated in conjunction with other criteria, when murine GWAS results are evaluated.
... Netrin-1 is important for development and plasticity in mesocorticolimbic dopamine neurons, which regulate the rewarding effects of many drugs of abuse, including opioids [99]. A screen of morphine-related phenotypes in inbred mouse strains identified Dcc, a gene encoding a Netrin-1 receptor [100]. Haplotypes in Dcc were associated with changes in morphine tolerance and the development of hyperalgesia [100]. ...
... A screen of morphine-related phenotypes in inbred mouse strains identified Dcc, a gene encoding a Netrin-1 receptor [100]. Haplotypes in Dcc were associated with changes in morphine tolerance and the development of hyperalgesia [100]. ...
Opioid abuse during pregnancy can result in Neonatal Opioid Withdrawal Syndrome (NOWS). We investigated genome-wide methylation analyses of 96 placental tissue samples, including 32 prenatally opioid-exposed infants with NOWS who needed therapy (+Opioids/+NOWS), 32 prenatally opioid-exposed infants with NOWS who did not require treatment (+Opioids/-NOWS), and 32 prenatally unexposed controls (-Opioids/-NOWS, control). Statistics, bioinformatics, Artificial Intelligence (AI), including Deep Learning (DL), and Ingenuity Pathway Analyses (IPA) were performed. We identified 17 dysregulated pathways thought to be important in the pathophysiology of NOWS and reported accurate AI prediction of NOWS diagnoses. The DL had an AUC (95% CI) =0.98 (0.95–1.0) with a sensitivity and specificity of 100% for distinguishing NOWS from the +Opioids/-NOWS group and AUCs (95% CI) =1.00 (1.0–1.0) with a sensitivity and specificity of 100% for distinguishing NOWS versus control and + Opioids/-NOWS group versus controls. This study provides strong evidence of methylation dysregulation of placental tissue in NOWS development.
... The expression of DCC was upregulated by repeated exposure to stimulant drugs in mesolimbic dopamine neurons, which was necessary for drug-induced structural plasticity [Flores, 2011]. In addition, DCC regulated tolerance, dependence, and hyperalgesia after chronic opioid exposure [Liang et al., 2014]. Therefore, DCC, which exhibits altered expression in response to morphine abuse, may play an important role in the susceptibility to drug dependence. ...
DCC netrin 1 receptor (DCC) affects the structure and function of the dopamine circuitry, which in turn affects the susceptibility to developing addiction. In a previous study, we found that single nucleotide polymorphism (SNP) rs12607853 in the 3' untranslated region (3'-UTR) of DCC was significantly associated with heroin addiction. In the current study, we first used bioinformatics prediction to identify the DCC rs12607853 C allele as a potential hsa-miR-422a and hsa-miR-378c target site. We then used vector construction and dual-luciferase reporter assays to investigate the targeting relationship of DCC rs12607853 with hsa-miR-422a and hsa-miR-378c. The dual-luciferase reporter gene assay confirmed that the C allele of rs12607853 in combination with hsa-miR-422a led to repressed dual-luciferase gene expression. Moreover, gene expression assays disclosed that hsa-miR-422a inhibited DCC expression at both the mRNA and protein levels. We also found that morphine inhibited the expression of hsa-miR-422a but increased the expression of DCC mRNA, and this change in the expression of hsa-miR-422a could not be reversed by naloxone, which suggested that the role of DCC in opioid addiction might be regulated by hsa-miR-422a. In summary, this study improves our understanding of the role of hsa-miR-422a and identifies the genetic basis of rs12607853, which might contribute to the discovery of new biomarkers or therapeutic targets for opioid addiction.
... 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]. ...
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.
... Известно, что рецептор нетрин-1 (netrin-1, анг.), кодируемый геном Dcc у мышей, также влияет на риск развития ОИГ и опиоидной толерантности. Взрослые мыши, гетерозиготные по мутациям в гене Dcc, имели значительно меньшую тенденцию к развитию OИГ, но становились толерантными или демонстрировали зависимость от хронического воздействия морфина [42]. ...
The role of mechanisms of the onset of opioid-induced hyperalgesia in patients with chronic pain syndrome of oncological genesis is highlighted according to the review of results of the search for Russian and English articles in the scientific bases of PubMed, Scopus, Web of Science, eLibrary. The importance of genetic factors predetermining the development of opioid-induced hyperalgesia is shown. The key role of pharmacological preparations for relief of chronic pain in the conditions of opioid-induced hyperalgesia is presented.
... Sensitizing amphetamine pretreatment regimens result in selective upregulation of the expression of DCC in the ventral tegmental area of adult rodents [18], and DCC haploinsufficiency decreases sensitivity to the cocaine mediated enhancement of reward seeking behavior [19]. Furthermore, DCC is a regulator of maladaptive responses, such as tolerance, dependence and opioid-induced hyperalgesia to chronic morphine administration [20]. On the basis of these findings, these four genes may be important mediators of drug addiction. ...
Recent studies have shown that variants in FAT atypical cadherin 3 (FAT3), kinectin 1 (KTN1), discs large homolog2 (DLG2) and deleted in colorectal cancer (DCC) genes influence the structure of the human mesolimbic reward system. We conducted a systematic analysis of the potential functional single nucleotide polymorphisms (SNPs) in these genes associated with heroin addiction. We scanned the functional regions of these genes and identified 20 SNPs for genotyping by using the SNaPshot method. A total of 1080 samples, comprising 523 cases and 557 controls, were analyzed. We observed that DCC rs16956878, rs12607853, and rs2292043 were associated with heroin addiction. The T alleles of rs16956878 (p = 0.0004) and rs12607853 (p = 0.002) were significantly enriched in the case group compared with the controls. A lower incidence of the C allele of rs2292043 (p = 0.002) was observed in the case group. In block 2 of DCC (rs2292043-rs12607853-rs16956878), the frequency of the T-T-T haplotype was significantly higher in the case group than in the control group (p = 0.024), and fewer C-C-C haplotypes (p = 0.006) were detected in the case group. DCC may be an important candidate gene in heroin addiction, and rs16956878, rs12607853, and rs2292043 may be risk factors, thereby providing a basis for further genetic and biological research.
... The influence of the genetic background on OIH has been clearly demonstrated in rodent models. Liang and colleagues have compared 23 strains of inbred mice in a chronic morphine protocol (40 mg/kg/d for 4 days), and have found strain differences for OIH (Liang et al., 2006(Liang et al., , 2014b. As an example, C57BL/6J mice displayed a strong hyperalgesia whereas 129/S mice developed no or a weak OIH under a same morphine protocol (Liang et al., 2006(Liang et al., , 2014bOladosu et al., 2015). ...
... Liang and colleagues have compared 23 strains of inbred mice in a chronic morphine protocol (40 mg/kg/d for 4 days), and have found strain differences for OIH (Liang et al., 2006(Liang et al., , 2014b. As an example, C57BL/6J mice displayed a strong hyperalgesia whereas 129/S mice developed no or a weak OIH under a same morphine protocol (Liang et al., 2006(Liang et al., , 2014bOladosu et al., 2015). Furthermore, single nucleotide polymorphisms at the multi-PDZ-domain protein 1 (MPDZ/ MUPP1) gene may contribute to this mouse strain variation in OIH, as the SNPs correlated with the OIH phenotypes, and heterozygous mutant mice for MPDZ displayed less morphine-induced hyperalgesia (Donaldson et al., 2016). ...
Opioids produce strong analgesia but their use is limited by a paradoxical hypersensitivity named opioid-induced hyperalgesia (OIH) that may be associated to analgesic tolerance. In the last decades, a significant number of preclinical studies have investigated the factors that modulate OIH development as well as the cellular and molecular mechanisms underlying OIH. Several factors have been shown to influence OIH including the genetic background and sex differences of experimental animals as well as the opioid regimen. Mu opioid receptor (MOR) variants and interactions of MOR with different proteins were shown important. Furthermore, at the cellular level, both neurons and glia play a major role in OIH development. Several neuronal processes contribute to OIH, like activation of neuroexcitatory mechanisms, long-term potentiation (LTP) and descending pain facilitation. Increased nociception is also mediated by neuroinflammation induced by the activation of microglia and astrocytes. Neurons and glial cells exert synergistic effects, which contribute to OIH. The molecular actors identified include the Toll-like receptor 4 and the anti-opioid systems as well as some other excitatory molecules, receptors, channels, chemokines, pro-inflammatory cytokines or lipids. This review summarizes the intracellular and intercellular pathways involved in OIH and highlights some mechanisms that may be challenged to limit OIH in the future.
