Bromodomain-containing Protein 4 Activates Voltage-gated Sodium Channel 1.7 Transcription in Dorsal Root Ganglia Neurons to Mediate Thermal Hyperalgesia in Rats

2017 ◽  
Vol 127 (5) ◽  
pp. 862-877 ◽  
Author(s):  
Ming-Chun Hsieh ◽  
Yu-Cheng Ho ◽  
Cheng-Yuan Lai ◽  
Hsueh-Hsiao Wang ◽  
An-Sheng Lee ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Thermal Hyperalgesia ◽  
Complete Freund’S Adjuvant ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Freund’S Adjuvant ◽  
Complete Freund's Adjuvant ◽  
Freund's Adjuvant

Abstract Background Bromodomain-containing protein 4 binds acetylated promoter histones and promotes transcription; however, the role of bromodomain-containing protein 4 in inflammatory hyperalgesia remains unclear. Methods Male Sprague–Dawley rats received hind paw injections of complete Freund’s adjuvant to induce hyperalgesia. The dorsal root ganglia were examined to detect changes in bromodomain-containing protein 4 expression and the activation of genes involved in the expression of voltage-gated sodium channel 1.7, which is a key pain-related ion channel. Results The intraplantar complete Freund’s adjuvant injections resulted in thermal hyperalgesia (4.0 ± 1.5 s; n = 7). The immunohistochemistry and immunoblotting results demonstrated an increase in the bromodomain-containing protein 4–expressing dorsal root ganglia neurons (3.78 ± 0.38 fold; n = 7) and bromodomain-containing protein 4 protein levels (2.62 ± 0.39 fold; n = 6). After the complete Freund’s adjuvant injection, histone H3 protein acetylation was enhanced in the voltage-gated sodium channel 1.7 promoter, and cyclin-dependent kinase 9 and phosphorylation of RNA polymerase II were recruited to this area. Furthermore, the voltage-gated sodium channel 1.7–mediated currents were enhanced in neurons of the complete Freund’s adjuvant rats (55 ± 11 vs. 19 ± 9 pA/pF; n = 4 to 6 neurons). Using bromodomain-containing protein 4–targeted antisense small interfering RNA to the complete Freund’s adjuvant–treated rats, the authors demonstrated a reduction in the expression of bromodomain-containing protein 4 (0.68 ± 0.16 fold; n = 7), a reduction in thermal hyperalgesia (7.5 ± 1.5 s; n = 7), and a reduction in the increased voltage-gated sodium channel 1.7 currents (21 ± 4 pA/pF; n = 4 to 6 neurons). Conclusions Complete Freund’s adjuvant triggers enhanced bromodomain-containing protein 4 expression, ultimately leading to the enhanced excitability of nociceptive neurons and thermal hyperalgesia. This effect is likely mediated by the enhanced expression of voltage-gated sodium channel 1.7.

DNA Hydroxymethylation by Ten-eleven Translocation Methylcytosine Dioxygenase 1 and 3 Regulates Nociceptive Sensitization in a Chronic Inflammatory Pain Model

2017 ◽  
Vol 127 (1) ◽  
pp. 147-163 ◽  
Author(s):  
Zhiqiang Pan ◽  
Zhou-Ya Xue ◽  
Guo-Fang Li ◽  
Meng-Lan Sun ◽  
Ming Zhang ◽  
...  
Keyword(s):  
Thermal Hyperalgesia ◽  
Complete Freund’S Adjuvant ◽  
Epigenetic Mechanism ◽  
Regulatory Function ◽  
Dna Hydroxymethylation ◽  
Nociceptive Information ◽  
Freund’S Adjuvant ◽  
Complete Freund's Adjuvant ◽  
Freund's Adjuvant ◽  
Group 5

Abstract Background Ten-eleven translocation methylcytosine dioxygenase converts 5-methylcytosine in DNA to 5-hydroxymethylcytosine, which plays an important role in gene transcription. Although 5-hydroxymethylcytosine is enriched in mammalian neurons, its regulatory function in nociceptive information processing is unknown. Methods The global levels of 5-hydroxymethylcytosine and ten-eleven translocation methylcytosine dioxygenase were measured in spinal cords in mice treated with complete Freund’s adjuvant. Immunoblotting, immunohistochemistry, and behavioral tests were used to explore the downstream ten-eleven translocation methylcytosine dioxygenase-dependent signaling pathway. Results Complete Freund’s adjuvant-induced nociception increased the mean levels (± SD) of spinal 5-hydroxymethylcytosine (178 ± 34 vs. 100 ± 21; P = 0.0019), ten-eleven translocation methylcytosine dioxygenase-1 (0.52 ± 0.11 vs. 0.36 ± 0.064; P = 0.0088), and ten-eleven translocation methylcytosine dioxygenase-3 (0.61 ± 0.13 vs. 0.39 ± 0.08; P = 0.0083) compared with levels in control mice (n = 6/group). The knockdown of ten-eleven translocation methylcytosine dioxygenase-1 or ten-eleven translocation methylcytosine dioxygenase-3 alleviated thermal hyperalgesia and mechanical allodynia, whereas overexpression cytosinethem in naïve mice (n = 6/group). Down-regulation of spinal ten-eleven translocation methylcytosine dioxygenase-1 and ten-eleven translocation methylcytosine dioxygenase-3 also reversed the increases in Fos expression (123 ± 26 vs. 294 ± 6; P = 0.0031; and 140 ± 21 vs. 294 ± 60; P = 0.0043, respectively; n = 6/group), 5-hydroxymethylcytosine levels in the Stat3 promoter (75 ± 16.1 vs. 156 ± 28.9; P = 0.0043; and 91 ± 19.1 vs. 156 ± 28.9; P = 0.0066, respectively; n = 5/group), and consequent Stat3 expression (93 ± 19.6 vs. 137 ± 27.5; P = 0.035; and 72 ± 15.2 vs. 137 ± 27.5; P = 0.0028, respectively; n = 5/group) in complete Freund’s adjuvant-treated mice. Conclusions This study reveals a novel epigenetic mechanism for ten-eleven translocation methylcytosine dioxygenase-1 and ten-eleven translocation methylcytosine dioxygenase-3 in the modulation of spinal nociceptive information via targeting of Stat3.

scholarly journals Functional Analysis of a Voltage-Gated Sodium Channel and Its Splice Variant from Rat Dorsal Root Ganglia

2002 ◽  
Vol 70 (6) ◽  
pp. 2262-2272 ◽  
Author(s):  
Paul S. Dietrich ◽  
Joseph G. McGivern ◽  
Stephen G. Delgado ◽  
Bruce D. Koch ◽  
Richard M. Eglen ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Sodium Channel ◽  
Dorsal Root Ganglia ◽  
Splice Variant ◽  
Dorsal Root ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated

scholarly journals Gene Knockdown of the N -Methyl-d-Aspartate Receptor NR1 Subunit with Subcutaneous Small Interfering RNA Reduces Inflammation-induced Nociception in Rats

2010 ◽  
Vol 112 (6) ◽  
pp. 1482-1493 ◽  
Author(s):  
Ping-Heng Tan ◽  
Yuan-Yi Chia ◽  
Lok-Hi Chow ◽  
Jieh-Jie Chen ◽  
Lin-Cheng Yang ◽  
...  
Keyword(s):  
Nervous System ◽  
Dorsal Root Ganglion ◽  
Subcutaneous Injection ◽  
Messenger Rna ◽  
Dorsal Root ◽  
Complete Freund’S Adjuvant ◽  
Aspartate Receptor ◽  
Freund’S Adjuvant ◽  
Complete Freund's Adjuvant ◽  
Freund's Adjuvant

Background Spinal N-methyl-D-aspartate receptors have been demonstrated to play an important role in the facilitation and maintenance of nociception. To avoid adverse effects of blocking N-methyl-D-aspartate receptors in the central nervous system, blocking N-methyl-D-aspartate receptor in peripheral nervous system is an ideal alternative. Transfection of small interfering RNAs (siRNAs) into cells has been revealed to provide potent silencing of specific genes. In this study, the authors examined the effect of subcutaneous injection of siRNA targeting the NR1 subunit of the N-methyl-D-aspartate receptor on silencing NR1 gene expression and subsequently abolishing inflammatory nociception in rats. Methods Male Sprague-Dawley rats received intradermal injection of NR1 siRNA and underwent injection of formalin or complete Freund's adjuvant. The flinch response and mechanical hypersensitivity by von Frey filaments were assessed. Then the messenger RNA and protein of NR1 in skin and dorsal root ganglion were analyzed. Results The results revealed that subcutaneous injection of 1 nmol NR1 siRNA effectively diminished the nociception induced by formalin and complete Freund's adjuvant stimuli and attenuated the level of NR1 messenger RNA and protein in skin and ipsilateral dorsal root ganglion. The antinociception effect and the inhibition of NR1 expression persisted for about 7 days after administration of NR1 siRNA. Conclusions The data of this study suggest that NR1 siRNA has potential therapeutic value in the treatment of inflammatory pain induced or maintained by peripheral nociceptor activity and support the potential application of this method to the study of nociceptive processes and target the validation of pain-associated genes.

A tetrodotoxin-resistant voltage-gated sodium channel from human dorsal root ganglia, hPN3/SCN10A

Pain ◽  
1998 ◽  
Vol 78 (2) ◽  
pp. 107-114 ◽  
Author(s):  
Douglas K. Rabert ◽  
Bruce D. Koch ◽  
Mariola Ilnicka ◽  
Rena A. Obernolte ◽  
Susan L. Naylor ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated
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