Prescription Opioid Misuse: Comparison
View Latest Version
Please note this is a comparison between Version 3 by Camila Xu and Version 2 by Camila Xu.

Prescription opioids are used for some chronic pain conditions. However, generally, long-term therapy has unwanted side effects which may trigger addiction, overdose, and eventually cause deaths. Opioid addiction and chronic pain conditions have both been associated with evidence of genetic and epigenetic alterations.

  • epigenetics
  • prescription opioids
  • pain

1. Introduction

Chronic pain represents significant public health concerns and prescription opioids are a common treatment option for cancer pain management, for end-of-life treatment, in relation to surgery, and for short-term use in severe acute/chronic pain conditions not related to cancer [1]. The non-medical use of opioids and their negative health consequences among people who use drugs have been studied since 2007 after the spread of the opioid crisis. However, in the last few years, we have witnessed a new opioid crisis, even among young people and categories of workers, particularly in North America, the Middle East, Asia, and Africa. This crisis is related to the non-medical use of prescription opioids that can result in opioid misuse, defined as “use contrary to the directed or prescribed pattern of use, regardless of the presence or absence of harm or adverse effects” [2]. Signs of an increase in methadone, buprenorphine, fentanyl, codeine, morphine, tramadol, and oxycodone misuse and the increased prescription rates for opioids for pain management have also been observed in Europe resulting in an increase of vulnerable cohorts of long-term opioid users [3]. The central issue is that long-term opioid therapy is associated with many side effects such as addiction, development of tolerance, and opioid-induced hyperalgesia. In addition, in 2018 more than one-third of overdose deaths involved pharmaceutical opioids with the number of overdose deaths rising from 3442 in 1999 to 17,029 in 2017 [4,5][4][5].

Opioid drugs act not only in nociceptive processes but also in modulating gastrointestinal, endocrine, and autonomic functions, as well as in affecting cognition and reward systems [6]. The relationship between pain states and substance abuse/misuse has been recently examined. Opioids carried an increased susceptibility to abuse even during initial exposure for pain treatment; in particular, when too many opioid drugs are prescribed for conditions not supposed to be treated by opioids or if healthcare systems are not set up to control the number of opioid prescriptions to an individual patient (doctor shopping) [7,8,9][7][8][9].

Nevertheless, it is important to note that the lack of consistent findings regarding the identification of personal risk factors that may predict opioid misuse in chronic pain patients was recently evidenced in the literature [10]. Among the possible risk factors, the individual genetic variability in conjunction with chronic pain, both affecting stress and reward systems, lead to differential responses to opioids and may determine the transition risk from therapeutic use to opioid addiction. Addiction is a multifactorial condition as both genetics and psychosocial factors can trigger opioid addictive behaviors. Polymorphisms in the μ -opioid receptor 1 ( OPRM1 ), the cytochrome P450 2D6 ( CYP2D6 ), the catechol-O-methyl transferase ( COMT ) genes and in the ATP-binding cassette family genes have been found to be associated with differences in morphine consumption and metabolization process [11]. The main environmental factors important for developing opioid/substance abuse are described as psychiatric medication prescriptions, mood disorders, specific mental health diagnoses, and adverse childhood experiences [12,13][12][13].

The aim of this review was to report the collected data from published studies on the identified epigenetic modifications associated with opioid prescription and misuse in patients who have initiated prescribed opioids for pain.

2. Specifics

All the publications collected in the literature search phase underwent abstract screening to determine eligibility for full-text data extraction. To be eligible for data extraction, studies met the following inclusion criteria: (1) the selected publications were in English language only; (2) the samples were composed of animal models to study chronic pain or human subjects with chronic noncancer pain (persistent pain lasting longer than 3 months), (3) participants were exposed to or were using prescription opioids, (4) the abstract listed one or more of the following terms in reference to potential epigenetic changes: DNA methylation, histone, chromatin, non-coding RNAs, microRNAs, gene or protein expression. Studies related to genetic polymorphisms, which are changes in the DNA sequence, were excluded from the review.

Finally, to identify potentially relevant studies not detected through the main screening, a few articles were selected from other reviews.

A thorough screening of the collected papers was conducted based on the inclusion criteria and quality of the experiments (methods typology to detect the epigenetic changes, adequate description of study methodology, sample size, and inclusion/exclusion criteria). Analyzing the identified papers, three main categories were evidenced and grouped in Table 1 , Table 2 and Table 3 , respectively: (i) studies investigating epigenetic changes in animal models (16), (ii) studies involving human subjects (3), and (iii) studies related to intergenerational or transgenerational prescribed opioid effects (5). Among the three studies on human subjects, one was related to cancer pain patients [35][14]. Nevertheless, it was included because considered relevant.

Table 1.
Epigenetic changes after prescribed opioid exposure in experimental models.
Opioids Tissues/Sample Epigenetic Methods Change Animals Findings PMID Authors
32
]
[
30
]
Table 2.
Epigenetic changes after prescribed opioid exposure in humans.
Opioids Tissues Epigenetic Methods Change Sample Findings PMID Authors
Morphine Brain tissues
Table 3.
Intergenerational/transgenerational prescribed opioid effects.
Opioids Tissues/Sample Epigenetic Methods Change Organism Findings PMID Authors


(PAG, PFC, temporal lobe, and ventral striatum) Microarray gene expression profiling and pattern matching Gene expression Adult male mice The development of tolerance is influenced by a region in OPRM1 gene. The genes epigenetically modified by chronic morphine administration are mainly related to neuroadaptation. 19386926 Tapocik et al., 2009 [17] Whole blood[15]
Bisulfite modification and Array-based genome-wide DNA methylation assay DNA methylation at specific CpG sites 140 opioid dependence cases and 80 opioid-exposed controls Three genome-wide significant differentially methylated CpGs map to genes involved in chromatin remodeling, DNA binding, cell survival, and cell projection (PARG, RERE, and CFAP77 genes). 31801960 Montalvo-Ortiz et al., 2019 [33
Oxycodone Rat brains] Quantitative RT-PCR[ Gene expression31] Timed pregnant Sprague-Dawley rats Exposed rat pups have lower birth weight and postnatal weight gain and greater congenital malformations. Endothelin B receptor expression is altered in the brain of oxycodone-treated rat pups indicating a possible delay in CNS(central nervous system) development. 26676852 Devarapalli et al., 2016 [36][33]
Morphine NAc Chromatin immunoprecipitation followed by massive parallel sequencing H3K9me2 distribution in NAc in the absence and presence of chronic morphine 9 to 11-week-old C57BL/6J male mice or G9afl/fl mice Chronic morphine decreases G9a expression and H3K9me2 at global level and in specific loci in mouse NAc. 23197736 Sun et al., 2012 [18][16]
Morphine
Opioid medication self-administration (hydrocodone, oxycodone, and codeine: 5–30 mg) Saliva collected at 3 time points Genome-wide DNA methylation assay and candidate approach DNA methylation at OPRM1 gene promoter 33 opioid-naïve participants who underwent standard dental surgery Hypermethylation of the OPRM1
Methadone or buprenorphine Cord blood or saliva Sequencing of bisulfite-treated DNA Determination of Percent DNA Methylation 86 infants with Neonatal Abstinence Syndrome from mothers receiving methadone or buprenorphine during pregnancy High methylation of three specific CpG sites of the OPRM1 promoter identified is associated with a worse outcome for Neonatal Abstinence Syndrome. 24996986 Wachman et al., 2014 [37][34] Central nucleus of amygdala Chromatin immunoprecipitation Gene and protein expression Female mice with persistent and acute pain Persistent pain and repeated morphine upregulate the transcriptional regulator MeCP2. MeCP2 enhances BDNF expression and represses G9a action and its repressive mark H3K9me2 in CeA. 24990928
OxycodoneZhang et al., 2014 [19 Brain-derived extracellular vesicle][17]
RNA sequencing MicroRNA expression Male and female Sprague Dawley rats Distinct miRNA signatures are identified in brain-derived extracellular vesicle at a key stage of brain development in offspring that were in utero and postnatal oxycodone-exposed. 31861723 Shahjin et al. 2019 [38][35] Morphine Central nucleus of amygdala Chromatin immunoprecipitation Gene expression Rat model of morphine self-administration The repression of GluA1 function by MeCp2 is proposed as a mechanism for morphine-seeking behavior in pain experience.
Morphine NAc Quantitative RT-PCR Gene expression Female Sprague-Dawley rats25716866 Hou et al., 2015 [20 Increased expression of KOR (K opioid receptor gene) and DRD2 (Dopamine 2 receptor gene) in response to repeated administration of quinpirole (a D2/D3 receptors agonist) in the progeny of females exposed to opiates during adolescence (also observed in the F2 generations).][18]
23314440 Byrnes et al., 2013 [39][36] Morphine Dorsal root ganglia and spinal cord tissues Quantitative RT-PCR, Western Immunoblotting and ChIP-PCR Gene and protein expression, histone modifications analysis Male Sprague-Dawley rats SNL (spinal nerve ligation) model G9a contributes to transcriptional repression of MORs in primary sensory neurons in neuropathic pain. G9a inhibitors: potential treatment of chronic neuropathic pain 26917724 Zhang et al., 2016 [21][19]
Morphine self-administration NAc RNA deep sequencing and qPCR Gene expression Female adolescent Sprague Dawley rats Genes related to synaptic plasticity and the myelin basic protein are dysregulated; some effects persisted into the subsequent generation. 27729240 Vassoler et al., 2017 [40][37] Morphine Dorsal root ganglia Quantitative RT-PCR and Western Blot Gene and protein expression Adult male CD-1 mice Neuropathic pain increases C/EBPβ expression. C/EPBβ activates the G9a gene, that epigenetically silences Kv1.2 and MOR genes. Blocking the induced increase in C/EBPβ in the DRG, morphine analgesia after CCI is improved. 28698219 Li et al., 2017 [22][20]
Morphine Basolateral amygdala Quantitative RT-PCR and Western Blot Gene and protein expression Male Sprague–Dawley Increase in H3K14ac together with upregulation of the BDNF and FosB; and CREB activation. 24829091 Wang et al., 2015 [23][21]
24][22]
Morphine, phentayl Hippocampus RNAseq Gene and protein expression Mice chronically treated with μ-opioid agonists The increased expression of MiR-339-3p inhibits intracellular MOR biosynthesis and acts as a negative feedback modulator of MOR signals. 23085997 Wu et al., 2013 [25][23]
Morphine Dorsal root ganglia Quantitative RT-PCR and Western Blot Gene and protein expression Male CD-1 mice treated with morphine to establish systemic chronic tolerance to morphine anti-nociception MiR-219 contributes to the development of chronic tolerance to morphine analgesia by targeting CaMKIIγ and enhancing CaMKIIγ-dependent brain-derived neurotrophic factor expression. 27599867 Hu et al., 2016 [26][24]
Morphine Dorsal root ganglia Quantitative RT-PCR and Western Blot Gene and protein expression Male CD-1 mice injected with morphine to elicit morphine tolerance The increased BDNF expression is regulated by the miR-375 and JAK2/STAT3 pathway. Inhibition of this pathway decreases BDNF production, and thus, attenuated morphine tolerance. 28603428 Li et al., 2017 [27][25]
promoter is measured in response to opioid use, and such epigenetic restructuring can be induced even by short-term use of therapeutic opioids. 32493461 Sandoval-Sierra et al., 2020 [34][32]
Remifentanil, oxycodone, codeine Whole blood Pyrosequencing at specific CpG sites and LINE1 (global genome-wide DNA methylation assay) DNA methylation 140 women with persistent pain after breast cancer surgery The global DNA methylation is shown to be a pain predictive biomarker, providing useful information to allocate the patients to either a “persistent pain” or “non-persistent pain” phenotype. 31775878 Kringel et al., 2019 [ Morphine Rat brain regions Pyrosequencing DNA methylation (5mC) and global DNA 5-hydroxymethylation (5hmC) Male Wistar rats Acute and chronic exposure is associated with significantly decreased/increased 5mC at specific genes (BDNF, IL1B, IL6, NR3C1, COMT Oxycodone Ventral tegmental area of the developing brain Quantitative RT-PCR and chromatin immunoprecipitation Gene expression and histone modifications analysis Male offspring of C57Bl/6NTac mice Adolescent oxycodone exposure increases the repressive mark H3K27me3, at key dopamine-related genes. 33325096 Carpenter et al., 2020 [28][26]
Oxycodone Striatum (NAc and CPu) RNAseq Gene expression Mice following extended 14-day oxycodone self-administration Alterations in the expression of

heterodimer receptor, integrins, semaphorins, semaphorin receptors, plexins, selective axon guidance genes.		 29946272 Yuferov et al., 2018 [29][27]
35][14] ). Global 5hmC levels increase in the cerebral cortex, hippocampus, and hypothalamus, but decrease in the midbrain. 29111854 Barrow et al., 2017 [ Oxycodone Dorsal striatum and ventral striatum RNAseq Gene expression Adult male C57BL/6J mice underwent a 14-day oxycodone self-administration Inflammation/immune genes have altered expression during chronic self-administration of oxycodone 28653080 Zhang et al., 2017 [30][28]
Oxycodone Hippocampus DNA ELISA Kit for total 5mC; quantitative RT-PCR Global 5mC levels and gene expression Male Sprague-Dawley rats The global DNA hypomethylation induced by oxycodone can be reversed through oxytocin and could significantly attenuate the oxycodone rewarding effects. 31526808 Fan et al., 2019 [31][29]
Oxycodone Ventral tegmental area DNA ELISA Kit for total 5mC and OneStep qMethyl™ kit for gene-specific 5mC, quantitative RT-PCR, Western blotting Global and specific 5mC levels and gene expression Sprague-Dawley rats Down-regulation of DNMT1 and up-regulation of TET1-3 lead to a decrease in global 5mC levels and differential demethylation at exon 1 of SYN and exon 2 of PSD95. 31735530 Fan et al., 2019
Opioids
[

Moreover, within the three subgroups, the articles were listed in the tables by the type of opioids (morphine, oxycodone, etc.). It thus became clear that the identified studies primarily investigated the morphine exposure effect on gene expression and chromatin modifications. Among the studies exploring oxycodone exposure in animal models, experiments measuring DNA methylation and DNA hydroxymethylation were selected. The few studies that considered these effects on human subjects were focused on DNA methylation. Interestingly, the screening revealed a group of articles related to the intergenerational and transgenerational effects of the epigenetic marks identified. Hence, the related remarkable information was described in a dedicated paragraph. In light of the few human studies identified, a paragraph about the epigenetic research related to heroin users was included to represent how these modifications have been studied in human subjects and to give future directions for the prescription opioid research related to different pain conditions.

3. ReOpioidsults

The nociceptive response was demonstrated to activate these epigenetic mechanisms by modulating pain genes and possibly mediating the transition from acute to chronic pain. Studies highlight that also opioids are involved in diverse types of epigenetic regulation and thus they might influence the analgesic effects or the increased risk of continued opioid intake and development of a substance use disorder following long-term opioid therapy [57,58][38][39].

Other studies focused on the rewarding effects of the widely abused prescription drug oxycodone, exploring related gene expression and DNA methylation changes after a period of chronic oxycodone self-administration. In particular, RNA-sequencing in the NAc and caudate-putamen (CPu) of mice following extended 14-day oxycodone self-administration revealed differential expression of the axon guidance molecule integrins, semaphorins, and ephrins, which may correspond to alterations in the axon-target connections and synaptogenesis and thus to the oxycodone-induced neuroadaptations [29][27]. In addition, levels of numerous glial-specific and immune cell-specific genes were also found to be altered in the CPu and NAc consistent with a previous study identifying altered expression of genes related to the inflammation and immune functions [30][28]. Furthermore, two interesting studies in the rat VTA and hippocampus, respectively, demonstrated that the oxycodone induction of CPP acquisition was associated with changes in gene expression and DNA methylation. Specifically, a down-regulation of DNMT1 and up-regulation of TET1-3 were observed in the VTA leading to a decrease in global DNA methylation levels and differential demethylation of the SYN and PSD95 genes with consistent higher expression of these synaptic proteins and the synaptic density [32][30]. In the hippocampus, global hypomethylation, higher synaptic density, and increased expression of specific synaptic genes, SYNAPSIN, SHANK2 , and GAP4 , were observed, too [31][29]. In addition, these studies suggested the therapeutic potential of oxytocin to prevent oxycodone addiction. In fact, oxytocin pretreatment markedly inhibited the acquisition of oxycodone CPP and restrained stress-induced reinstatement of oxycodone. Consistently, the synaptic density and the global DNA hypomethylation induced by oxycodone were normalized and the transcription of synaptic genes and DNA methylation enzyme genes was restored [31,32][29][30].

The studies investigating intergenerational and transgenerational epigenetic changes following prescription opioid exposure are reported in Table 3 .

The role of miRNAs, 18-25 nucleotide non-coding sequences with a wide range of regulatory roles in gene expression and neuronal functions, was also investigated in heroin-seeking behavior. MiR-218 was found to regulate many neuroplasticity-related genes and target the methyl CpG-binding protein 2 (Mecp2), thus inhibiting heroin-induced reinforcement [56][40].

References

  1. Dowell, D.; Haegerich, T.M.; Chou, R. CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016. Recomm. Rep. 2016, 65, 1–49.
  2. Vowles, K.E.; McEntee, M.L.; Julnes, P.S.; Frohe, T.; Ney, J.P.; van der Goes, D.N. Rates of opioid misuse, abuse, and addiction in chronic pain: A systematic review and data synthesis. Pain 2015, 156, 569–576.
  3. UNODC. World Drug Report 2020 (United Nations Publication, Sales No. E.20.XI.6); UNODC: Vienna, Austria, 2020.
  4. Fishbain, D.A.; Cole, B.; Lewis, J.; Rosomoff, H.L.; Rosomoff, R.S. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drug-related behaviors? A structured evidence-based review. Pain Med. 2008, 9, 444–459.
  5. Centers for Disease Control and Prevention (CDC) Wide-Ranging Online Data for Epidemiologic Research (WONDER). National Center for Health Statistics. Available online: http://wonder.cdc.gov (accessed on 30 September 2020).
  6. Trescot, A.M.; Datta, S.; Lee, M.; Hansen, H. Opioid pharmacology. Pain Physician 2008, 11, S133–S153.
  7. Manhapra, A.; Becker, W.C. Pain and Addiction: An Integrative Therapeutic Approach. Med. Clin. N. Am. 2018, 102, 745–763.
  8. Biernikiewicz, M.; Taieb, V.; Toumi, M. Characteristics of doctor-shoppers: A systematic literature review. J. Mark. Access Health Policy 2019, 7, 1595953.
  9. Volkow, N.; Benveniste, H.; McLellan, A.T. Use and Misuse of Opioids in Chronic Pain. Annu. Rev. Med. 2018, 69, 451–465.
  10. Voon, P.; Karamouzian, M.; Kerr, T. Chronic pain and opioid misuse: A review of reviews. Subst. Abuse Treat. Prev. Policy 2017, 12, 36.
  11. Vieira, C.M.P.; Fragoso, R.M.; Pereira, D.; Medeiros, R. Pain polymorphisms and opioids: An evidence based review. Mol. Med. Rep. 2019, 19, 1423–1434.
  12. Klimas, J.; Gorfinkel, L.; Fairbairn, N.; Amato, L.; Ahamad, K.; Nolan, S.; Simel, D.L.; Wood, E. Strategies to Identify Patient Risks of Prescription Opioid Addiction When Initiating Opioids for Pain: A Systematic Review. JAMA Netw. Open 2019, 2, e193365.
  13. Merrick, M.T.; Ford, D.C.; Haegerich, T.M.; Simon, T. Adverse Childhood Experiences Increase Risk for Prescription Opioid Misuse. J. Prim. Prev. 2020, 41, 139–152.
  14. Kringel, D.; Kaunisto, M.A.; Kalso, E.; Lötsch, J. Machine-learned analysis of global and glial/opioid intersection-related DNA methylation in patients with persistent pain after breast cancer surgery. Clin. Epigenet. 2019, 11, 167.
  15. Tapocik, J.D.; Letwin, N.; Mayo, C.L.; Frank, B.; Luu, T.; Achinike, O.; House, C.; Williams, R.; Elmer, G.I.; Lee, N.H. Identification of candidate genes and gene networks specifically associated with analgesic tolerance to morphine. J. Neurosci. 2009, 29, 5295–5307.
  16. Sun, H.; Maze, I.; Dietz, D.M.; Scobie, K.N.; Kennedy, P.J.; Damez-Werno, D.; Neve, R.L.; Zachariou, V.; Shen, L.; Nestler, E.J. Morphine epigenomically regulates behavior through alterations in histone H3 lysine 9 dimethylation in the nucleus accumbens. J. Neurosci. 2012, 32, 17454–17464.
  17. Zhang, Z.; Tao, W.; Hou, Y.-Y.; Wang, W.; Kenny, P.J.; Pan, Z.Z. MeCP2 repression of G9a in regulation of pain and morphine reward. J. Neurosci. 2014, 34, 9076–9087.
  18. Hou, Y.-Y.; Cai, Y.-Q.; Pan, Z.Z. Persistent pain maintains morphine-seeking behavior after morphine withdrawal through reduced MeCP2 repression of GluA1 in rat central amygdala. J. Neurosci. 2015, 35, 3689–3700.
  19. Zhang, Y.; Chen, S.-R.; Laumet, G.; Chen, H.; Pan, H.-L. Nerve Injury Diminishes Opioid Analgesia through Lysine Methyltransferase-mediated Transcriptional Repression of μ-Opioid Receptors in Primary Sensory Neurons. J. Biol. Chem. 2016, 291, 8475–8485.
  20. Li, Z.; Mao, Y.; Liang, L.; Wu, S.; Yuan, J.; Mo, K.; Cai, W.; Mao, Q.; Cao, J.; Bekker, A.; et al. The transcription factor C/EBPβ in the dorsal root ganglion contributes to peripheral nerve trauma-induced nociceptive hypersensitivity. Sci. Signal. 2017, 10.
  21. Wang, Y.; Lai, J.; Cui, H.; Zhu, Y.; Zhao, B.; Wang, W.; Wei, S. Inhibition of histone deacetylase in the basolateral amygdala facilitates morphine context-associated memory formation in rats. J. Mol. Neurosci. 2015, 55, 269–278.
  22. Barrow, T.M.; Byun, H.-M.; Li, X.; Smart, C.; Wang, Y.-X.; Zhang, Y.; Baccarelli, A.A.; Guo, L. The effect of morphine upon DNA methylation in ten regions of the rat brain. Epigenetics 2017, 12, 1038–1047.
  23. Wu, Q.; Hwang, C.K.; Zheng, H.; Wagley, Y.; Lin, H.-Y.; Kim, D.K.; Law, P.-Y.; Loh, H.H.; Wei, L.-N. MicroRNA 339 down-regulates μ-opioid receptor at the post-transcriptional level in response to opioid treatment. FASEB J. 2013, 27, 522–535.
  24. Hu, X.-M.; Cao, S.-B.; Zhang, H.-L.; Lyu, D.-M.; Chen, L.-P.; Xu, H.; Pan, Z.-Q.; Shen, W. Downregulation of miR-219 enhances brain-derived neurotrophic factor production in mouse dorsal root ganglia to mediate morphine analgesic tolerance by upregulating CaMKIIγ. Mol. Pain 2016, 12, 1744806916666283.
  25. Li, H.; Tao, R.; Wang, J.; Xia, L. Upregulation of miR-375 level ameliorates morphine analgesic tolerance in mouse dorsal root ganglia by inhibiting the JAK2/STAT3 pathway. J. Pain Res. 2017, 10, 1279–1287.
  26. Carpenter, M.D.; Manners, M.T.; Heller, E.A.; Blendy, J.A. Adolescent oxycodone exposure inhibits withdrawal-induced expression of genes associated with the dopamine transmission. Addict. Biol. 2020, e12994.
  27. Yuferov, V.; Zhang, Y.; Liang, Y.; Zhao, C.; Randesi, M.; Kreek, M.J. Oxycodone Self-Administration Induces Alterations in Expression of Integrin, Semaphorin and Ephrin Genes in the Mouse Striatum. Front. Psychiatry 2018, 9, 257.
  28. Zhang, Y.; Liang, Y.; Levran, O.; Randesi, M.; Yuferov, V.; Zhao, C.; Kreek, M.J. Alterations of expression of inflammation/immune-related genes in the dorsal and ventral striatum of adult C57BL/6J mice following chronic oxycodone self-administration: A RNA sequencing study. Psychopharmacology 2017, 234, 2259–2275.
  29. Fan, X.-Y.; Shi, G.; Zhao, P. Reversal of oxycodone conditioned place preference by oxytocin: Promoting global DNA methylation in the hippocampus. Neuropharmacology 2019, 160, 107778.
  30. Fan, X.-Y.; Shi, G.; Zhao, P. Methylation in Syn and Psd95 genes underlie the inhibitory effect of oxytocin on oxycodone-induced conditioned place preference. Eur. Neuropsychopharmacol. 2019, 29, 1464–1475.
  31. Montalvo-Ortiz, J.L.; Cheng, Z.; Kranzler, H.R.; Zhang, H.; Gelernter, J. Author Correction: Genomewide Study of Epigenetic Biomarkers of Opioid Dependence in European- American Women. Sci. Rep. 2019, 9, 18774.
  32. Sandoval-Sierra, J.V.; Salgado García, F.I.; Brooks, J.H.; Derefinko, K.J.; Mozhui, K. Effect of short-term prescription opioids on DNA methylation of the OPRM1 promoter. Clin. Epigenet. 2020, 12, 76.
  33. Devarapalli, M.; Leonard, M.; Briyal, S.; Stefanov, G.; Puppala, B.L.; Schweig, L.; Gulati, A. Prenatal Oxycodone Exposure Alters CNS Endothelin Receptor Expression in Neonatal Rats. Drug Res. (Stuttg) 2016, 66, 246–250.
  34. Wachman, E.M.; Hayes, M.J.; Lester, B.M.; Terrin, N.; Brown, M.S.; Nielsen, D.A.; Davis, J.M. Epigenetic variation in the mu-opioid receptor gene in infants with neonatal abstinence syndrome. J. Pediatr. 2014, 165, 472–478.
  35. Shahjin, F.; Guda, R.S.; Schaal, V.L.; Odegaard, K.; Clark, A.; Gowen, A.; Xiao, P.; Lisco, S.J.; Pendyala, G.; Yelamanchili, S.V. Brain-Derived Extracellular Vesicle microRNA Signatures Associated with In Utero and Postnatal Oxycodone Exposure. Cells 2019, 9, 21.
  36. Byrnes, J.J.; Johnson, N.L.; Carini, L.M.; Byrnes, E.M. Multigenerational effects of adolescent morphine exposure on dopamine D2 receptor function. Psychopharmacology 2013, 227, 263–272.
  37. Vassoler, F.M.; Oliver, D.J.; Wyse, C.; Blau, A.; Shtutman, M.; Turner, J.R.; Byrnes, E.M. Transgenerational attenuation of opioid self-administration as a consequence of adolescent morphine exposure. Neuropharmacology 2017, 113, 271–280.
  38. Niederberger, E.; Resch, E.; Parnham, M.J.; Geisslinger, G. Drugging the pain epigenome. Nat. Rev. Neurol. 2017, 13, 434–447.
  39. Banerjee, G.; Edelman, E.J.; Barry, D.T.; Becker, W.C.; Cerdá, M.; Crystal, S.; Gaither, J.R.; Gordon, A.J.; Gordon, K.S.; Kerns, R.D.; et al. Non-medical use of prescription opioids is associated with heroin initiation among US veterans: A prospective cohort study. Addiction 2016, 111, 2021–2031.
  40. Yan, B.; Hu, Z.; Yao, W.; Le, Q.; Xu, B.; Liu, X.; Ma, L. MiR-218 targets MeCP2 and inhibits heroin seeking behavior. Sci. Rep. 2017, 7, 40413.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Feedback