Epigenetic upregulation of metabotropic glutamate receptor 2 in the spinal cord attenuates oestrogen-induced visceral hypersensitivity

Cao, Dong-Yuan; Bai, Guang; Ji, Yaping; Traub, Richard J.

doi:10.1136/gutjnl-2014-307748

Cited by 64 publications

(57 citation statements)

References 32 publications

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“…In addition, SAHA up-regulated the expression of mGlu2 receptors in the DRG, which was associated with increased acetylation of p65/RelA (Chiechio et al, 2009). Interestingly, data consistent with these observations were also recently reported in a rat model of estrogen-induced visceral hypersensitivity (Cao et al, 2014). In addition, Bai et al found that pre-injection of SAHA (1 = 25 g, intrathecal) significantly delayed the thermal hyperalgesia induced by unilateral CFA injection in the hind paw and that intrathecal injection with 25 g of SAHA attenuated existing thermal hyperalgesia 24 h after CFA injection.…”

Section: Hydroxamatessupporting

confidence: 68%

Is there any therapeutic value for the use of histone deacetylase inhibitors for chronic pain?

Wang

Cui

Ling

et al. 2016

Brain Research Bulletin

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Section: Hydroxamatessupporting

confidence: 68%

Is there any therapeutic value for the use of histone deacetylase inhibitors for chronic pain?

Wang

Cui

Ling

et al. 2016

Brain Research Bulletin

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“…In this regard Ralya and McCarson (Ralya and McCarson, 2014) showed that a surge in serum estrogen can produce a stimulus-intensity-dependent increase in inflammation-evoked nociceptive behavior, which is consistent with the findings of Lu and coworkers (Lu et al, 2012) showing that systemic application of estriol, as well as 17β-estradiol (E 2 ), increases hyperalgesia in CFA-induced chronic pain. In addition, (Zhang et al, 2012) showed that spinal administration of E 2 produces mechanical allodynia and thermal hyperalgesia in both male and female rats confirming the local spinal effect of E 2 , while Cao et al (Cao et al, 2014) demonstrated that spinal E 2 facilitates the visceromotor response to colorectal distention.…”

Section: Discussionmentioning

confidence: 90%

Colocalization of aromatase in spinal cord astrocytes: Differences in expression and relationship to mechanical and thermal hyperalgesia in murine models of a painful and a non-painful bone tumor

et al. 2015

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While spinal cord astrocytes play a key role in the generation of cancer pain, there have been no studies that have examined the relationship of tumor-induced astrocyte activation and aromatase expression during the development of cancer pain. Here, we examined tumor-induced mechanical hyperalgesia and cold allodynia, and changes in GFAP and aromatase expression in murine models of painful and non-painful bone cancer. We demonstrate that implantation of fibrosarcoma cells, but not melanoma cells, produces robust mechanical hyperalgesia and cold allodynia in tumor-bearing mice compared to saline-injected controls. Secondly, this increase in mechanical hyperalgesia and cold allodynia is mirrored by significant increases in both spinal astrocyte activity and aromatase expression in the dorsal horn of fibrosarcoma-bearing mice. Importantly, we show that aromatase is only found within a subset of astrocytes and not in neurons in the lumbar spinal cord. Finally, administration of an aromatase inhibitor reduced tumor-induced hyperalgesia in fibrosarcoma-bearing animals. We conclude that a painful fibrosarcoma tumor induces a significant increase in spinal astrocyte activation and aromatase expression and that the up-regulation of aromatase plays a role in the development of bone tumor-induced hyperalgesia. Since spinal aromatase is also upregulated, but to a lesser extent, in non-painful melanoma bone tumors, it may also be neuroprotective and responsive to the changing tumor environment.

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“…104 Another estrogenmediated mechanism that could drive visceral hypersensitivity is via the induction of µ-opioid receptor internalization within the medial preoptic nucleus and the posterodorsal medial amygdala. 105 At the level of the spinal cord, multiple studies have characterized estrogen as an important modulator of visceral nociceptive signaling, specifically through an effect on the N-methyl-D-aspartate receptor, 106 metabotropic glutamate receptor 2 (mGluR2), 107 and ionotropic glutamate receptor subunit 2B activity 108 within the spinal cord.…”

Section: Sex Linked Differences In Visceral Sensitivitymentioning

confidence: 99%

“…127 Furthermore, in a model of visceral hypersensitivity induced by 17β-estradiol in female rats, SAHA infused on to the lumbosacral spinal cord lead to hyperacetylation of H3K9 at the promoter for the metabotropic glutamate receptor-2 (mGLuR2). 107 Counter intuitively, the SAHA-induced increase in mGluR2 expression inhibited the estradiol-induced visceral hypersensitivity. 107 Evidence from models of chronic cystitis or esophageal reflux disease identified several miRNAs associated with chronic visceral pain.…”

Section: Epigenetic Mechanisms That Contribute To Irritable Bowel Synmentioning

confidence: 99%

“…107 Counter intuitively, the SAHA-induced increase in mGluR2 expression inhibited the estradiol-induced visceral hypersensitivity. 107 Evidence from models of chronic cystitis or esophageal reflux disease identified several miRNAs associated with chronic visceral pain. 128,129 In a series of pivotal studies, Zhou and coworkers determined the importance of miR-29 on visceral hypersensitivity via a mechanism involving increased intestinal permeability.…”

Section: Epigenetic Mechanisms That Contribute To Irritable Bowel Synmentioning

confidence: 99%

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Mechanisms of Stress-induced Visceral Pain

Meerveld

Johnson

2018

J Neurogastroenterol Motil

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Evidence suggests that long-term stress facilitates visceral pain through sensitization of pain pathways and promotes chronic visceral pain disorders such as the irritable bowel syndrome (IBS). This review will describe the importance of stress in exacerbating IBS-induced abdominal pain. Additionally, we will briefly review our understanding of the activation of the hypothalamic-pituitary-adrenal axis by both chronic adult stress and following early life stress in the pathogenesis of IBS. The review will focus on the glucocorticoid receptor and corticotropin-releasing hormone-mediated mechanisms in the amygdala involved in stress-induced visceral hypersensitivity. One potential mechanism underlying persistent effects of stress on visceral sensitivity could be epigenetic modulation of gene expression. While there are relatively few studies examining epigenetically mediated mechanisms involved in stress-induced visceral nociception, alterations in DNA methylation and histone acetylation patterns within the brain, have been linked to alterations in nociceptive signaling via increased expression of pro-nociceptive neurotransmitters. This review will discuss the latest studies investigating the long-term effects of stress on visceral sensitivity. Additionally, we will critically review the importance of experimental models of adult stress and early life stress in enhancing our understanding of the basic molecular mechanisms of nociceptive processing. Taken together, the complex clinical phenotype makes recapitulating IBS in rodent models extremely challenging. However, an aim of this review will be to describe how the use of rodent models of adult stress, early life stress (ELS), and a dysregulated HPA axis has improved our understanding of stress in the pathophysiology of IBS. Pathophysiology of Irritable Bowel Syndrome: Activation of the Brain-Gut AxisEvidence from clinical and basic research points to dysregulation of the bidirectional communication between the brain-gut axis in IBS. 21 The brain-gut axis represents a dynamic interplay between central circuits and peripheral mechanisms. The messengers of this complex circuit include neural, endocrine, metabolic, and immune mediators that are activated by central factors such as stress (Fig. 1). Although IBS is not an inflammatory disorder, the immune system plays a role in the pathogenesis of IBS in at least a subset of patients and likely contributes to the etiology of IBS symptoms. 22,23 A subset of IBS patients display a low grade chronic inflammation, and there is also evidence that following an enteric infection and combined with stressful life events, there is an increased risk of developed post-infectious IBS. [24][25][26][27] Clearly, the immune system and inflammatory processes are modulated by the HPA and autonomic nervous systems. In support, IBS patients also show increased number and reactivity of mast cells. 28,29 Data from peripheral blood mononuclear cells, as well as in mucosal biopsies, from IBS patients show that cytokines levels including TNF-α...

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Epigenetic upregulation of metabotropic glutamate receptor 2 in the spinal cord attenuates oestrogen-induced visceral hypersensitivity

Cited by 64 publications

References 32 publications

Is there any therapeutic value for the use of histone deacetylase inhibitors for chronic pain?

Is there any therapeutic value for the use of histone deacetylase inhibitors for chronic pain?

Colocalization of aromatase in spinal cord astrocytes: Differences in expression and relationship to mechanical and thermal hyperalgesia in murine models of a painful and a non-painful bone tumor

Mechanisms of Stress-induced Visceral Pain

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