Pannexin-1 Up-regulation in the Dorsal Root Ganglion Contributes to Neuropathic Pain Development

Zhang, Yuhao; Laumet, Geoffroy; Chen, Shao‐Rui; Hittelman, Walter N.; Pan, Hui Lin

doi:10.1074/jbc.m115.650218

Cited by 88 publications

(103 citation statements)

References 49 publications

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“…In some SNL rats, G9a-specific siRNA (4 g) or the negative control siRNA was administered intrathecally. G9a-specific siRNA (AGUAACG-GGCAUCAAUGC) or universal negative control siRNA (SIC001, Sigma-Aldrich) was mixed with i-Fect (Neuromics, Edina, MN) to a final concentration of 400 mg/liter for the intrathecal injections (21,25).…”

Section: Methodsmentioning

confidence: 99%

“…To determine which histone modification is involved in the silencing of Oprm1 expression after nerve injury, we performed ChIP followed by quantitative PCR (ChIP-PCR) to determine how SNL alters different histone marks at the promoter regions of Oprm1 in the DRG. We selected two activating histone marks, H3K4me3 and H3K9ac (39 -41), and two repressive histone marks, H3K9me2 and H3K27me3 (42,43), because these four marks are predictive of gene expression in the DRG (21,25). SNL caused a large increase in the occupancy of H3K9me2 in all three promoter regions of Oprm1 in the DRG (Fig.…”

Section: Nerve Injury Consistently Increases H3k9me2 Levels In the Oprm1mentioning

confidence: 99%

“…Because intrathecal injections bring agents in direct contact with DRG neurons (21,25), we treated the animals with daily intrathecal injections of 10 g of UNC0638, a highly specific G9a/GLP inhibitor (44), or vehicle for 7 days. The efficacy and specificity of intrathecal UNC0638 had been confirmed by quantifying H3K9me2 and other histone marks in our recent in vivo study (21).…”

Section: Inhibition Of G9a Restores Mor Expression and Rescues The Momentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: Nerve Injury Consistently Increases H3k9me2 Levels In the Oprm1mentioning

confidence: 99%

Section: Inhibition Of G9a Restores Mor Expression and Rescues The Momentioning

confidence: 99%

See 1 more Smart Citation

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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“…Nerve injury increased expression of Panx1 in dorsal root ganglia, and Panx1 knockdown reduced caspase-1 release and hyperalgesia. 87 Panx1 has recently been proposed to be the cell membrane pore induced by P2X7R activation, and this in turn may activate the NALP1 inflammasome in astrocytes and neurons. 88 89 Thus, targeting purinergic signalling may reduce pain in part by reducing inflammasome activation.…”

mentioning

confidence: 99%

The inflammasome as a target for pain therapy

Zhang¹,

Li²,

Li³

et al. 2016

British Journal of Anaesthesia

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The interleukin-1 family of cytokines are potent inducers of inflammation and pain. Proteolytic activation of this family of cytokines is under the control of several innate immune receptors that coordinate to form large multiprotein signalling platforms, termed inflammasomes. Recent evidence suggests that a wide range of inflammatory diseases, cancers, and metabolic and autoimmune disorders, in which pain is a common complaint, may be coordinated by inflammasomes. Activation of inflammasomes results in cleavage of caspase-1, which subsequently induces downstream initiation of several potent pro-inflammatory cascades. Therefore, it has been proposed that targeting inflammasome activity may be a novel and effective therapeutic strategy for these pain-related diseases. The purpose of this narrative review article is to provide the reader with an overview of the activation and regulation of inflammasomes and to investigate the potential therapeutic role of inflammasome inhibition in the treatment of diseases characterized by pain, including the following: complex regional pain syndrome, gout, rheumatoid arthritis, inflammatory pain, neuropathic pain, chronic prostatitis, chronic pelvic pain syndrome, and fibromyalgia. We conclude that the role of the inflammasome in pain-associated diseases is likely to be inflammasome subtype and disease specific. The currently available evidence suggests that disease-specific targeting of the assembly and activity of the inflammasome complex may be a novel therapeutic opportunity for the treatment of refractory pain in many settings.

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“…Physiologically, Panx-1 channels are mainly involved in the efflux of ATP and regulate cellular inflammasomes [4]. Many studies indicated that Panx-1 is related to epilepsy, neuropathic pain, painful musculoskeletal diseases, ischemia injury, myocardial fibrosis, overactivity of the human bladder, and cancers [5][6][7][8][9][10][11][12][13] (Fig. 1 ).…”

mentioning

confidence: 99%

A new perspective of mechanosensitive pannexin-1 channels in cancer metastasis: clues for the treatment of other stress-induced diseases

2016

ABBS

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Cancer metastasis is a process that cancer cells deviate from the primary site and spread to the other areas to form new colonies, which is the leading cause of death in cancer patients. During metastatic progression, circulating cancer cells lodge within the microvasculature of end organs, where most of them die from mechanical deformation. However, cancer cells can survive from mechanical deformation by unknown mechanisms. Recently, Furlow et al.[1] identified a mutation truncated form of pannexin-1 (Panx-1), PANX1 1-89 , which was significantly enriched in highly metastatic cancer cells. PANX1 augmented Panx-1 channel-mediated adenosine triphosphate (ATP) release and enhanced the efficiency of metastasis by promoting metastatic breast cancer cells survival during physical deformation. Additionally, carbenoxolone (CBX), a Panx-1 inhibitor, was proved to reduce the efficiency of breast cancer metastasis. These results suggested that Panx-1 is one of the molecular bases for metastatic cell survival in microvasculature-induced biomechanical trauma [1]. In 2000, three members of pannexins, including Panx-1, Panx-2, and Panx-3, have been found to be new members of gap-junctions' family [2]. Panx-1 was ubiquitously expressed in human tissues. Subsequent studies further revealed that Panx-1 forms single-pass membrane channels that connect the intracellular and extracellular compartments rather than forming intercellular channels spanning the two plasma membranes, which is mainly different from classical gap junctions [3]. Physiologically, Panx-1 channels are mainly involved in the efflux of ATP and regulate cellular inflammasomes [4]. Many studies indicated that Panx-1 is related to epilepsy, neuropathic pain, painful musculoskeletal diseases, ischemia injury, myocardial fibrosis, overactivity of the human bladder, and cancers [5][6][7][8][9][10][11][12][13] (Fig. 1 ).The beneficial or aggravating role of Panx-1 in cancer remains controversial. Lai et al. [5] reported that Panx-1 plays a tumor-suppressive role in vitro and in vivo. Reverse transcription polymerase chain reaction analysis revealed that C6 cells do not express Panx-1. However, stable expression of Panx-1 in C6 glioma cells significantly inhibits cell growth, proliferation, and motility in vitro [5]. Besides, Panx-1 is an important intratumor biomechanical environment regulator that accelerates the dynamic assembly of multicellular C6 glioma aggregates [6]. Panx-1 also significantly reduces the tumor size in athymic nude mice [5,6]. Derangere et al. [7] reported that caspase-1-dependent colon cancer cell pyroptosis is mainly induced through the interaction with Panx-1. These data supported that Panx-1 has a tumorsuppressor property, while some other studies indicated that Panx-1 promotes the development of cancer. Penuela et al. [8] found that Panx-1 is upregulated in B16 melanoma cells rather than in normal melanocytes. Furthermore, Panx-1-depleted B16 melanoma cells exhibit reduced cell migration and growth, resembling normal melanocytes. Knockdown o...

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Pannexin-1 Up-regulation in the Dorsal Root Ganglion Contributes to Neuropathic Pain Development

Cited by 88 publications

References 49 publications

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

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

The inflammasome as a target for pain therapy

A new perspective of mechanosensitive pannexin-1 channels in cancer metastasis: clues for the treatment of other stress-induced diseases

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