Histone deacetylase inhibitors relieve morphine resistance in neuropathic pain after peripheral nerve injury

Uchida, Hitoshi; Matsushita, Yosuke; Araki, Kohei; Mukae, Takehiro; Ueda, Hiroshi

doi:10.1016/j.jphs.2015.07.040

Cited by 32 publications

(21 citation statements)

References 14 publications

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“…DNA methylation represses gene transcription through several mechanisms including physically blocking the binding of transcription factors and/or functioning as docking sites for transcriptional repressors/corepressors192021222324. How DNMTs contribute to neuropathic pain genesis is still elusive, although other epigenetic mechanisms (for example, histone modifications and non-coding RNAs) have recently been implicated in rodent models of neuropathic pain19252627282930313233.…”

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confidence: 99%

DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons

et al. 2017

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Nerve injury induces changes in gene transcription in dorsal root ganglion (DRG) neurons, which may contribute to nerve injury-induced neuropathic pain. DNA methylation represses gene expression. Here, we report that peripheral nerve injury increases expression of the DNA methyltransferase DNMT3a in the injured DRG neurons via the activation of the transcription factor octamer transcription factor 1. Blocking this increase prevents nerve injury-induced methylation of the voltage-dependent potassium (Kv) channel subunit Kcna2 promoter region and rescues Kcna2 expression in the injured DRG and attenuates neuropathic pain. Conversely, in the absence of nerve injury, mimicking this increase reduces the Kcna2 promoter activity, diminishes Kcna2 expression, decreases Kv current, increases excitability in DRG neurons and leads to spinal cord central sensitization and neuropathic pain symptoms. These findings suggest that DNMT3a may contribute to neuropathic pain by repressing Kcna2 expression in the DRG.

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confidence: 99%

DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons

et al. 2017

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“…Transcription factors, such as repressor element 1-silencing transcription factor may bind to the Oprm1 promoter to inhibit Oprm1 expression through histone deacetylases. Both histone deacetylase inhibi- tors and repressor element 1-silencing transcription factor knockdown can increase MOR expression levels and the morphine analgesic effect reduced by nerve injury (12,48), supporting this possibility. Because G9a is essential for silencing of repressor element 1-silencing transcription factor-regulated genes (49) and can regulate polycomb repressive complex 2 on histone H3K9 to mediate gene silencing (38), it is possible that G9a forms a repressive complex with repressor element 1-silencing transcription factor, histone deacetylases, DNA methyltransferases, and EZH2 at the Oprm1 promoter in the injured DRG.…”

Section: Discussionmentioning

confidence: 85%

Nerve Injury Diminishes Opioid Analgesia through Lysine Methyltransferase-mediated Transcriptional Repression of μ-Opioid Receptors in Primary Sensory Neurons

Zhang¹,

Chen²,

Laumet

et al. 2016

Journal of Biological Chemistry

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The -opioid receptor (MOR, encoded by Oprm1) agonists are the mainstay analgesics for treating moderate to severe pain. Nerve injury causes down-regulation of MORs in the dorsal root ganglion (DRG) and diminishes the opioid effect on neuropathic pain. However, the epigenetic mechanisms underlying the diminished MOR expression caused by nerve injury are not clear. G9a (encoded by Ehmt2), a histone 3 at lysine 9 methyltransferase, is a key chromatin regulator responsible for gene silencing. In this study, we determined the role of G9a in diminished MOR expression and opioid analgesic effects in animal models of neuropathic pain. We found that nerve injury in rats induced a long-lasting reduction in the expression level of MORs in the DRG but not in the spinal cord. Nerve injury consistently increased the enrichment of the G9a product histone 3 at lysine 9 dimethylation in the promoter of Oprm1 in the DRG. G9a inhibition or siRNA knockdown fully reversed MOR expression in the injured DRG and potentiated the morphine effect on pain hypersensitivity induced by nerve injury. In mice lacking Ehmt2 in DRG neurons, nerve injury failed to reduce the expression level of MORs and the morphine effect. In addition, G9a inhibition or Ehmt2 knockout in DRG neurons normalized nerve injury-induced reduction in the inhibitory effect of the opioid on synaptic glutamate release from primary afferent nerves. Our findings indicate that G9a contributes critically to transcriptional repression of MORs in primary sensory neurons in neuropathic pain. G9a inhibitors may be used to enhance the opioid analgesic effect in the treatment of chronic neuropathic pain.Chronic neuropathic pain resulting from damage to the peripheral or central nervous system causes agonizing suffering and reduced quality of life. Neuropathic pain is often resistant to conventional analgesic treatments and remains a major therapeutic challenge. Opioid drugs such as morphine produce their therapeutic effects through binding to the -opioid receptors (MORs, 3 encoded by Oprm1) (1, 2) and are widely used to treat moderate to severe pain. In patients with neuropathic pain, however, the analgesic potency of MOR agonists is reduced (3, 4). The opioid effects are also diminished in animal models of neuropathic pain (5-7). MORs expressed at primary sensory neurons and their central terminals in the spinal dorsal horn are essential for the analgesic effects of opioids (8 -10). Peripheral nerve injury reduces the expression level of MORs in the dorsal root ganglion (DRG), contributing to the loss of opioid analgesic efficacy in neuropathic pain (6,11,12). However, the epigenetic mechanisms by which nerve injury leads to diminished MOR expression in the DRG remain unclear.Transcriptional homeostasis is largely maintained by the dynamic balance between positive and negative regulation of gene transcription. Gene expression is critically controlled by chromatin structure and the modification status of histone tails (13-15). DNA methylation and histone modifications are two major ...

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“…SUV39H1 likely contributes to nerve injury-induced nociceptive hypersensitivity through epigenetic silencing of MOR in the injured DRG. Nerve injury-induced DRG MOR downregulation is also restored by the inhibition of DRG histone deacetylase or G9a 38;43;44 , suggesting multiple epigenetic mechanisms by which the MOR gene is silenced in the injured DRG after peripheral nerve injury. Compensation by other mechanisms may not occur, as blocking each mechanism can restore MOR expression in the injured DRG.…”

Section: Discussionmentioning

confidence: 99%

Contribution of the Suppressor of Variegation 3-9 Homolog 1 in Dorsal Root Ganglia and Spinal Cord Dorsal Horn to Nerve Injury–induced Nociceptive Hypersensitivity

et al. 2016

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Background Peripheral nerve injury–induced gene alterations in the dorsal root ganglion (DRG) and spinal cord likely participate in neuropathic pain genesis. Histone methylation gates gene expression. Whether the suppressor of variegation 3-9 homolog 1 (SUV39H1), a histone methyltransferase, contributes to nerve injury–induced nociceptive hypersensitivity is unknown. Methods Quantitative real-time reverse transcription polymerase chain reaction analysis, Western blot analysis, or immunohistochemistry were carried out to examine the expression of SUV39H1 mRNA and protein in rat DRG and dorsal horn and its colocalization with DRG μ-opioid receptor (MOR). The effects of a SUV39H1 inhibitor (chaetocin) or SUV39H1 siRNA on fifth lumbar spinal nerve ligation (SNL)–induced DRG MOR down-regulation and nociceptive hypersensitivity were examined. Results SUV39H1 was detected in neuronal nuclei of the DRG and dorsal horn. It was distributed predominantly in small DRG neurons, in which it coexpressed with MOR. The level of SUV39H1 protein in both injured DRG and ipsilateral fifth lumbar dorsal horn was time dependently increased after SNL. SNL also produced an increase in the amount of SUV39H1 mRNA in the injured DRG (n = 6/time point). Intrathecal chaetocin or SUV39H1 siRNA as well as DRG or intraspinal microinjection of SUV39H1 siRNA impaired SNL-induced allodynia and hyperalgesia (n = 5/group/treatment). DRG microinjection of SUV39H1 siRNA also restored SNL-induced DRG MOR down-regulation (n = 6/group). Conclusions The findings of this study suggest that SUV39H1 contributes to nerve injury–induced allodynia and hyperalgesia through gating MOR expression in the injured DRG. SUV39H1 may be a potential target for the therapeutic treatment of nerve injury–induced nociceptive hypersensitivity.

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Histone deacetylase inhibitors relieve morphine resistance in neuropathic pain after peripheral nerve injury

Cited by 32 publications

References 14 publications

DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons

DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons

Nerve Injury Diminishes Opioid Analgesia through Lysine Methyltransferase-mediated Transcriptional Repression of μ-Opioid Receptors in Primary Sensory Neurons

Contribution of the Suppressor of Variegation 3-9 Homolog 1 in Dorsal Root Ganglia and Spinal Cord Dorsal Horn to Nerve Injury–induced Nociceptive Hypersensitivity

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