Pain Medicine  |   November 2017
Bromodomain-containing Protein 4 Activates Voltage-gated Sodium Channel 1.7 Transcription in Dorsal Root Ganglia Neurons to Mediate Thermal Hyperalgesia in Rats
Author Notes
  • From the Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan (M.-C.H.); Department of Medicine, Mackay Medical College, New Taipei, Taiwan (M.-C.H., Y.-C.H., C.-Y.L., H.-H.W., A.-S.L., J.-K.C., Y.-P.C., H.-Y.P.); Department of Veterinary Medicine, College of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan (C.-Y.L.); and Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan (J.-K.C.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • M.-C.H. and Y.-C.H. contributed equally to this article.
    M.-C.H. and Y.-C.H. contributed equally to this article.×
  • Submitted for publication September 15, 2016. Accepted for publication June 29, 2017.
    Submitted for publication September 15, 2016. Accepted for publication June 29, 2017.×
  • Address correspondence to Dr. Peng: Department of Medicine, Mackay Medical College, No. 46, Sec. 3, Zhongzheng Road, Sanzhi District, New Taipei, Taiwan 25245. hsien.yu@gmail.com. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Basic Science / Central and Peripheral Nervous Systems / Pain Medicine
Pain Medicine   |   November 2017
Bromodomain-containing Protein 4 Activates Voltage-gated Sodium Channel 1.7 Transcription in Dorsal Root Ganglia Neurons to Mediate Thermal Hyperalgesia in Rats
Anesthesiology 11 2017, Vol.127, 862-877. doi:10.1097/ALN.0000000000001809
Anesthesiology 11 2017, Vol.127, 862-877. doi:10.1097/ALN.0000000000001809
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.