Drugging the pain epigenome

Niederberger, Ellen; Resch, Eduard; Parnham, Michael J.; Geißlinger, Gerd

doi:10.1038/nrneurol.2017.68

Cited by 65 publications

(45 citation statements)

References 196 publications

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“…One way in which cell function can be impacted over long periods of time is through epigenetics ( Denk and McMahon, 2017 ). Indeed, the role of epigenetic mechanisms is increasingly being studied in the pain field ( Denk et al, 2016 ; Denk and McMahon, 2017 ; Niederberger et al, 2017 ), as well as in neuroscience in general ( Akbarian et al, 2015 ; Gray et al, 2015 ; Mo et al, 2015 ; Halder et al, 2016 ; Hannon et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Negative Evidence for a Functional Role of Neuronal DNMT3a in Persistent Pain

Saunders

Hore

Gentry

et al. 2018

Front. Mol. Neurosci.

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Traditionally, neuroscience has had to rely on mixed tissue analysis to examine transcriptional and epigenetic changes in the context of nervous system function or pathology. However, particularly when studying chronic pain conditions, this approach can be flawed, since it neglects to take into account the shifting contribution of different cell types across experimental conditions. Here, we demonstrate this using the example of DNA methyltransferases (DNMTs) – a group of epigenetic modifiers consisting of Dnmt1, Dnmt3a, and Dnmt3b in mammalian cells. We used sensory neuron-specific knockout mice for Dnmt3a/3b as well as pharmacological blockade of Dnmt1 to study their role in nociception. In contrast to previous analyses on whole tissue, we find that Dnmt3a and 3b protein is not expressed in adult DRG neurons, that none of the DNA methyltransferases are regulated with injury and that interfering with their function has no effect on nociception. Our results therefore currently do not support a role for neuronal DNA methyltransferases in pain processing in adult animals.

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Section: Introductionmentioning

confidence: 99%

Negative Evidence for a Functional Role of Neuronal DNMT3a in Persistent Pain

Saunders

Hore

Gentry

et al. 2018

Front. Mol. Neurosci.

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“…Several preclinical studies showed amelioration of hyperalgesia or allodynia following pharmacological modulation of histone acetylation/deacetylation. 40,41 Fewer attempts have been made to therapeutically target DNA methylation – possibly due to the lack of drugs suitable for interfering with DNMTs function. Future studies may provide a deeper understanding of the activity and structure of the different DNMTs, enabling the development of specific inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic control of hypersensitivity in chronic inflammatory pain by the de novo DNA methyltransferase Dnmt3a2

et al. 2019

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Chronic pain is a pathological manifestation of neuronal plasticity supported by altered gene transcription in spinal cord neurons that results in long-lasting hypersensitivity. Recently, the concept that epigenetic regulators might be important in pathological pain has emerged, but a clear understanding of the molecular players involved in the process is still lacking. In this study, we linked Dnmt3a2, a synaptic activity-regulated de novo DNA methyltransferase, to chronic inflammatory pain. We observed that Dnmt3a2 levels are increased in the spinal cord of adult mice following plantar injection of Complete Freund’s Adjuvant, an in vivo model of chronic inflammatory pain. In vivo knockdown of Dnmt3a2 expression in dorsal horn neurons blunted the induction of genes triggered by Complete Freund’s Adjuvant injection. Among the genes whose transcription was found to be influenced by Dnmt3a2 expression in the spinal cord is Ptgs2, encoding for Cox-2, a prime mediator of pain processing. Lowering the levels of Dnmt3a2 prevented the establishment of long-lasting inflammatory hypersensitivity. These results identify Dnmt3a2 as an important epigenetic regulator needed for the establishment of central sensitization. Targeting expression or function of Dnmt3a2 may be suitable for the treatment of chronic pain.

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“…These epigenetic changes may contribute to the development of several pain symptoms and the manifestation of chronic pain. In addition to providing a valuable insight into the molecular mechanisms of pain development and chronic pain syndromes, some studies have provided evidence regarding the use of epigenetic modulation as a potential therapeutic option for cancer-related pain (91,93,94).…”

Section: Future Outlookmentioning

confidence: 99%