Early life adversity promotes sex-specific resilience to opioid addiction-related phenotypes
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PROVIDER: PRJNA673395 | ENA |
REPOSITORIES: ENA
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Project description:Early life stress that is not overwhelming can have an “inoculating” effect that promotes resilience in adulthood. However, the mechanisms underlying stress inoculation are unknown and animal models are lacking. Here we used the limited bedding and nesting (LBN) model of adversity to evaluate stress inoculation of addiction-related phenotypes. In LBN, pups from postnatal day 2–9 and their dams were exposed to a low resource environment. In adulthood, they were tested for addiction-like phenotypes and compared to rats raised in standard housing conditions. High levels of impulsivity are associated with substance abuse, but LBN reduced impulsive choice compared to controls in males. LBN males also self-administered less morphine and had a lower breakpoint on a progressive ratio reinforcement schedule than controls. LBN had no effect on addiction-related behavior in females. The nucleus accumbens (NAc) mediates these behaviors, so we tested whether LBN altered NAc physiology in drug-naïve and morphine-exposed rats. LBN reduced sEPSC frequency in males, but not females. Only in males, LBN prevented a morphine-induced increased in the AMPA/NMDA ratio. RNA sequencing and genome-wide assessments of histone modifications were performed to delineate the molecular signature in the NAc associated with LBN-derived phenotypes. LBN produced sex-specific changes in transcription, including in genes related to glutamate transmission. Remodeling of unique histone marks may have contributed to these distinct transcriptional profiles. Collectively, these studies reveal that LBN causes a male-specific stress inoculation effect against addiction-related phenotypes. Identifying factors that promote resilience to addiction may reveal novel treatment options for patients.
2021-02-04 | GSE160495 | GEO
Project description:Due to the current opioid epidemic, a better understanding of genetic and environmental factors that contribute to opioid addiction is warranted. To explore the potential causative role of VitD in opioid addiction , we used multiple pharmacologic approaches and genetic mouse models. We used profiled the transcriptome of key brain reward regions upon morphine treatment in vitamin D receptor KO and wild type mice. Our results highlight the role of VitD deficiency in the development of addiction and suggest a potential therapeutic benefit of VitD supplementation for VitD deficient individuals in the prevention and management of addiction.
2021-04-25 | GSE171683 | GEO
Project description: Not available
| S-EPMC7923376 | biostudies-literature
Project description:Vitamin D deficiency exacerbates UV/endorphin and opioid addiction
| PRJNA720566 | ENA
Project description:Background: Opioid withdrawal is a key driver of opioid addiction and an obstacle to recovery. However, withdrawal effects on opioid reinforcement and mesolimbic neuroadaptation are understudied and the role of sex is largely unknown. Methods: Male (n=13) and female (n=12) rats responded under a fentanyl-vs.-food “choice” procedure during daily 2h sessions. In addition to the daily choice sessions, rats were provided extended access to fentanyl during 12h self-administration sessions. After two weeks of this selfadministration regimen, the nucleus accumbens (NAc) and ventral tegmental area (VTA) of a subset of rats were subjected to RNA sequencing. In the remaining rats, a third week of this self-administration regimen was conducted, during which methadone effects on fentanyl-vs.-food choice were determined. Results: Prior to opioid dependence, male and female rats similarly allocated responding between fentanyl and food. Abstinence from extended fentanyl access elicited similar increases in somatic withdrawal signs in both sexes. Despite similar withdrawal signs and extended access fentanyl intake, opioid withdrawal was accompanied by a maladaptive increase in fentanyl choice in males, but not females. Behavioral sex differences corresponded with a greater number of differentially expressed genes in the NAc and VTA of opioidwithdrawn females relative to males. Methadone blocked withdrawal-associated increases in fentanyl choice in males, but failed to further decrease fentanyl choice in females. Conclusions: These results provide foundational evidence of sex-specific neuroadaptations to opioid withdrawal, which may be relevant to the female-specific resilience to withdrawal-associated increases in opioid choice and aid in the identification of novel therapeutic targets.
2021-05-06 | GSE173959 | GEO
Project description:Opioids analgesics are frequently prescribed in the United States and worldwide. However, serious side effects such as addiction, immunosuppression and gastrointestinal symptoms limit their use. It has been recently demonstrated that morphine treatment results in significant disruption in gut barrier function leading to increased translocation of gut commensal bacteria. Further study indicated distinct alterations in the gut microbiome and metabolome following morphine treatment, contributing to the negative consequences associated with opioid use. However, it is unclear how opioids modulate gut homeostasis in the context of a hospital acquired bacterial infection. In the current study, a mouse model of C. rodentium infection was used to investigate the role of morphine in the modulation of gut homeostasis in the context of a hospital acquired bacterial infection. Citrobacter rodentium is a natural mouse pathogen that models intestinal infection by enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) and causes attaching and effacing lesions and colonic hyperplasia. Morphine treatment resulted in 1) the promotion of C. rodentium systemic dissemination, 2) increase in virulence factors expression with C. rodentium colonization in intestinal contents, 3) altered gut microbiome, 4) damaged integrity of gut epithelial barrier function, 5) inhibition of C. rodentium-induced increase in goblet cells, and 6) dysregulated IL-17A immune response. This is the first study to demonstrate that morphine promotes pathogen dissemination in the context of intestinal C. rodentium infection, indicating morphine modulates virulence factor-mediated adhesion of pathogenic bacteria and induces disruption of mucosal host defense during C. rodentium intestinal infection in mice. This study demonstrates and further validates a positive correlation between opioid drug use/abuse and increased risk of infections, suggesting over-prescription of opioids may increase the risk in the emergence of pathogenic strains and should be used cautiously. Therapeutics directed at maintaining gut homeostasis during opioid use may reduce the comorbidities associated with opioid use for pain management.
2020-02-18 | E-MTAB-7503 | biostudies-arrayexpress
Project description:Drug addiction is a major threat to the public health in the US and many other countries. Opioid abuse is associated with increased risks for cancer, psychological complications, heart and lung disease, and infections of the liver and blood. Because metabolites are intrinsically involved in multiple metabolic pathways in vivo, the relative quantification of metabolites in body fluids (for example urine) can provide a profile of the metabolic state of an organism. Metabolomics is a powerful technique for revealing the impact of exposure on the overall biochemistry of an individual or system. Opioids can modify the output of urinary metabolites through many integrated neural and hormonal mechanisms within the periphery, central nervous system, and kidneys. Opioids modulate the expression of genes involved in neuroplasticity through epigenetic and possibly RNA modifications, ultimately change the intracellular signaling cascades and dysfunction, and cause long-lasting changes in metabolome. The objective of this study is to identify how opium impacts metabolic pathways to provide markers of abuse, long-term opium addiction, the addiction molecular pathway, and unknown metabolites that are important to differentiation of the study phenotypes. To reach these goals in the present study, the urine specimens of opium abusers and non-users as controls was profiled using an untargeted nuclear magnetic resonance spectroscopy (NMR) metabolomics platform at University of North Carolina at Chapel Hill. The Golestan Cohort Study is conducted in Northeast of Iran to primarily study the risk factors for upper gastrointestinal cancers in this high-risk region, in which about 50,000 volunteers were analyzed for opium users and their mortality. More than 8,000 of participants (17%) age 40-75 reported opium use with a mean duration of 12.7 years. Opium was either smoked or orally consumed. The participants were selected from the cohort stratified by opium use patterns and tobacco use.
2020-12-01 | ST001619 | MetabolomicsWorkbench
Project description:Drug addiction is a major threat to the public health in the US and many other countries. Opioid abuse is associated with increased risks for cancer, psychological complications, heart and lung disease, and infections of the liver and blood. Because metabolites are intrinsically involved in multiple metabolic pathways in vivo, the relative quantification of metabolites in body fluids (for example urine) can provide a profile of the metabolic state of an organism. Metabolomics is a powerful technique for revealing the impact of exposure on the overall biochemistry of an individual or system. Opioids can modify the output of urinary metabolites through many integrated neural and hormonal mechanisms within the periphery, central nervous system, and kidneys. Opioids modulate the expression of genes involved in neuroplasticity through epigenetic and possibly RNA modifications, ultimately change the intracellular signaling cascades and dysfunction, and cause long-lasting changes in metabolome. The objective of this study is to identify how opium impacts metabolic pathways to provide markers of abuse, long-term opium addiction, the addiction molecular pathway, and unknown metabolites that are important to differentiation of the study phenotypes. To reach these goals in the present study, the urine specimens of opium abusers and non-users as controls will be profiled using an untargeted liquid chromatography mass spectrometric (LC-MS/MS) at University of North Carolina at Chapel Hill. The Golestan Cohort Study is conducted in Northeast of Iran to primarily study the risk factors for upper gastrointestinal cancers in this high-risk region, in which about 50,000 volunteers were analyzed for opium users and their mortality. More than 8,000 of participants (17%) age 40-75 reported opium use with a mean duration of 12.7 years. Opium was either smoked or orally consumed. The participants were selected from the cohort stratified by opium use patterns and tobacco use.
2020-12-01 | ST001618 | MetabolomicsWorkbench
Project description:The opioid receptors are important regulators of pain, reward, and addiction. Limited evidence suggests the mu and delta opioid receptors form a heterodimer (MDOR), which may act as a negative feedback brake on opioid-induced analgesia. However, evidence for the MDOR in vivo is indirect and limited, and there are few selective tools available. We recently published the first MDOR-selective antagonist, D24M, allowing us to test the role of the MDOR in mice. We thus co-treated CD-1 mice with D24M and opioids in tail flick, paw incision, and chemotherapy-induced peripheral neuropathy pain models. D24M treatment enhanced oxymorphone anti-nociception in all models by 52.3%-628%. This enhancement could not be replicated with the mu and delta selective antagonists CTAP and naltrindole, and D24M had a mild transient effect in the Rotarod test, suggesting this increase is selective to the MDOR. However, D24M had no effect on morphine or buprenorphine, suggesting that only specific opioids interact with the MDOR. To find a mechanism we performed phosphoproteomic analysis on brainstems of mice. We found that the kinases Src and CaMKII were repressed by oxymorphone, which was restored by D24M. We were able to confirm the role of Src and CaMKII in D24M-enhanced anti-nociception using small molecule inhibitors (KN93, Src-I1). Together these results provide direct in vivo evidence that the MDOR acts as an opioid negative feedback brake, which occurs via the repression of Src and CaMKII signal transduction. These results further suggest that MDOR antagonism could be a means to improve clinical opioid therapy.
2023-03-10 | PXD022106 | Pride
Project description:Early life adversity has been linked to altered reproductive development in humans, including changes in the timing of pubertal onset and sexual activity. One common form of early life adversity is having limited access to resources. This form of early life adversity can be modeled in rodents using the limited bedding and nesting model (LBN), in which rat dams and pups are placed in a low resource environment from postnatal day (PND) 2 through 9. Our laboratory has previously shown that male rats raised in LBN conditions have elevated levels of plasma estradiol compared to control males. Female rats, on the other hand, show no effect of LBN on plasma hormone levels, pubertal timing, or estrous cycle duration in adulthood. Here, we find that LBN males also show changes in adult reproductive behaviors. LBN males acquired the suite of reproductive behaviors more quickly than their control counterparts over the course of 3 weeks of testing, showing shorter latencies to mount, intromit, and ejaculate compared to controls prior to the final week of testing. We also characterized LBN-induced gene transcription changes across sex in the medial preoptic area (mPOA) which underlies reproductive behaviors. Interestingly, there was no effect of LBN on puberty onset (as measured by preputial separation) or masculinization of the sexually dimorphic nucleus of the preoptic area (SDN/POA; as measured by calbindin immunoreactivity) in males, suggesting LBN may not exert effects on hormone-dependent measures until after puberty.
2022-02-15 | GSE174753 | GEO