Enrichment of Genomic Pathways Based on Differential DNA Methylation Associated With Chronic Postsurgical Pain and Anxiety in Children: A Prospective, Pilot Study

Chidambaran, Vidya; Zhang, Xue; Geisler, Kristie J; Stubbeman, Bobbie L.; Rothenberg, Marc E.; Weirauch, Matthew T.; Meller, Jarek; Ji, Hong

doi:10.1016/j.jpain.2018.12.008

Cited by 34 publications

(38 citation statements)

References 83 publications

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“…It is reported that treatment that promoted DNA demethylation might have resulted in mechanical and thermal antinociception in a mouse oral cancer model [24]. Furthermore, DNA methylation regulates several additional pain and analgesiarelated genes in various pain models [25]. Similarly, in our study, CCI increased DNA methylation in rats and timedependently increased expression of DNMT3a protein in ipsilateral L4 and L5 DRGs, especially on day 14.…”

Section: Discussionsupporting

confidence: 75%

DNA Methylation May be Involved in the Analgesic Effect of Hyperbaric Oxygen via Regulating FUNDC1

Liu

Gao

et al. 2020

Pain Research and Management

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Background. Neuropathic pain (NP) is a type of chronic pain which lacks predictable, effective, and safe therapeutic options. We investigated the role of hyperbaric oxygen (HBO) in expression of FUN14 domain-containing 1 (FUNDC1), which is associated with DNA methylation. Methods. We randomly divided rats into four groups: sham operation (S), S + HBO, chronic constriction injury (CCI), and CCI + HBO. Lumbar (L)4 and L5 dorsal root ganglia (DRGs) were used to assess expression of DNA methyltransferase (DNMT)1, DNMT3a, and DNMT3b by western blotting and RT-PCR. Pain-related behaviors were evaluated using mechanical withdrawal threshold and thermal withdrawal latency analysis. Western blotting was also used to assess expression of FUNDC1, BCL2, and adenovirus E1B19 kDa-interacting protein 3-like (NIX) and BCL2 and adenovirus E1B19 kDa-interacting protein3 (BNIP3). And we also examined the changes of FUNDC1 with immunofluorescence. Nonnucleoside DNA methyltransferase inhibitor RG108 was administered prior to CCI. The pain-related behavior and western blotting changes were examined in all groups. Results. DNMT3a expression was higher on day 14 after CCI. HBO downregulated DNMT3a mRNA and protein expression, but not those of DNMT1 and DNMT3b. HBO increased pain-related behavior significantly, while it was down-regulated by RG108. In HBO groups, FUNDC1, NIX, and BNIP3 expression was upregulated more significantly than in the CCI group. In addition, FUNDC1 protein colocalized with NeuN and rarely with glutamine synthetase. However, expression was reduced when RG108 was administered. Immunofluorescence showed that FUNDC1 was upregulated after HBO treatment. Conclusion. Our findings suggest that DNA methylation is involved in the analgesic effect of HBO via the regulation of FUNDC1.

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Section: Discussionsupporting

confidence: 75%

DNA Methylation May be Involved in the Analgesic Effect of Hyperbaric Oxygen via Regulating FUNDC1

Liu

Gao

et al. 2020

Pain Research and Management

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“…17,42,43 Recent studies in younger persons further suggest DNA methylation is associated with chronic pain susceptibility in humans. 18,19…”

Section: Discussionmentioning

confidence: 99%

Epigenetic aging is associated with clinical and experimental pain in community-dwelling older adults

et al. 2019

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Gerontological research reveals considerable interindividual variability in aging phenotypes, which has motivated research efforts to identify “aging biomarkers.” Aging biomarkers are used to calculate biological age, which are better predictors of disease risk and residual lifespan when compared to chronological age alone. Emerging evidence using the epigenetic clock as an aging biomarker supports highly reliable individualized predictions about future health. This study aimed to determine whether an epigenetic aging biomarker was associated with chronic pain in older adults (60–83 years old). A subset of participants (n = 29) in the Neuromodulatory Examination of Pain and Mobility Across the Lifespan study underwent a blood draw, demographic, psychological, cognitive, and pain assessments. We estimated Horvath’s epigenetic clock and calculated the difference between epigenetic age and chronological age that has been previously reported to predict overall mortality risk. Older individuals without chronic pain (n = 9) had significantly “younger” epigenetic age compared to those with chronic pain (n = 20, p < 0.05). Older epigenetic age was associated with greater pain during daily activities (r = 0.494, p = 0.010) and anatomical pain sites (r = 0.741, p < 0.001) but not pain frequency/duration. An older epigenetic age was also associated with higher vibratory detection thresholds (r = 0.490, p = 0.021), heat pain thresholds (r = −0.478, p = 0.028), and pressure pain thresholds at the trapezius (r = −0.571, p = 0.006) but not thermal detection, pressure pain at the quadriceps or pain inhibition (p’s > 0.05). Epigenetic aging was associated with greater emotional stability (r = −0.461, p = 0.027), conscientiousness (r = −0.549, p = 0.007), and lower extraversion (r = 0.414, p = 0.049) but not depression or affect (p’s > 0.05). Epigenetic aging was also associated with lower episodic (r = −0.698, p = 0.001) and working memory (r = −0.760, p < 0.001). Our findings suggest that chronic pain is associated with accelerated epigenetic aging in healthy, community-dwelling older individuals, and future studies with larger samples are needed to confirm our findings. An aging biomarker such as the epigenetic clock may help identify people with chronic pain at greater risk of functional decline and poorer health outcomes.

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“…DNA methylation is a characteristic and early-formed epigenetic mechanism in mammals that is primarily responsible for the stable expression of functional genes related to complex physical changes. 87 In a latest clinical prospective study, 88 the ingenuity pathway analysis of genes with DNA methylated positions for both chronic postsurgical pain and Child Anxiety Sensitivity Index revealed an enrichment of several canonical pathways, including GABA receptor, which supports GABA hypofunction contributing to the maintenance of pain. DNA methylation triggered by methyltransferases (DNMTs) inhibits gene expression.…”

Section: Mechanisms Of Neuropathy-related Gaba Plasticitymentioning

confidence: 98%

The etiological contribution of GABAergic plasticity to the pathogenesis of neuropathic pain

Lei

Tian

et al. 2019

Mol Pain

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Neuropathic pain developing after peripheral or central nerve injury is the result of pathological changes generated through complex mechanisms. Disruption in the homeostasis of excitatory and inhibitory neurons within the central nervous system is a crucial factor in the formation of hyperalgesia or allodynia occurring with neuropathic pain. The central GABAergic pathway has received attention for its extensive distribution and function in neural circuits, including the generation and development of neuropathic pain. GABAergic inhibitory changes that occur in the interneurons along descending modulatory and nociceptive pathways in the central nervous system are believed to generate neuronal plasticity, such as synaptic plasticity or functional plasticity of the related genes or proteins, that is the foundation of persistent neuropathic pain. The primary GABAergic plasticity observed in neuropathic pain includes GABAergic synapse homo- and heterosynaptic plasticity, decreased synthesis of GABA, down-expression of glutamic acid decarboxylase and GABA transporter, abnormal expression of NKCC1 or KCC2, and disturbed function of GABA receptors. In this review, we describe possible mechanisms associated with GABAergic plasticity, such as central sensitization and GABAergic interneuron apoptosis, and the epigenetic etiologies of GABAergic plasticity in neuropathic pain. Moreover, we summarize potential therapeutic targets of GABAergic plasticity that may allow for successful relief of hyperalgesia from nerve injury. Finally, we compare the effects of the GABAergic system in neuropathic pain to other types of chronic pain to understand the contribution of GABAergic plasticity to neuropathic pain.

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Enrichment of Genomic Pathways Based on Differential DNA Methylation Associated With Chronic Postsurgical Pain and Anxiety in Children: A Prospective, Pilot Study

Cited by 34 publications

References 83 publications

DNA Methylation May be Involved in the Analgesic Effect of Hyperbaric Oxygen via Regulating FUNDC1

DNA Methylation May be Involved in the Analgesic Effect of Hyperbaric Oxygen via Regulating FUNDC1

Epigenetic aging is associated with clinical and experimental pain in community-dwelling older adults

The etiological contribution of GABAergic plasticity to the pathogenesis of neuropathic pain

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