Pulsed Radiofrequency Attenuates Complete Freund's Adjuvant-Induced Epigenetic Suppression of Potassium Chloride Cotransporter 2 Expression

Chia Kai Liu, Wen Tzu Liao, Yu Chi Chu, Chien Hui Yang, Kuan Hung Chen, Chih Hsien Wu, Chung Ren Lin

Research output: Contribution to journalJournal Article peer-review

10 Scopus citations


Methods: Male Sprague-Dawley rats were injected with CFA into the plantar surface of the left hind paw to induce inflammation. PRF (20 minutes of 500-kHz RF pulses, delivered at a rate of 2 Hz, maximum temperature 42ºC) was delivered to the L5 and L6 anterior primary ramus just distal to the intervertebral foramen of adult CFA or saline rats. The hind paw withdrawal threshold to von Frey filament stimuli and withdrawal latency to radiant heat were determined before and after CFA. Acetyl-histone H3 and H4 was determined by chromatin immunoprecipitation in spinal dorsal horn. KCC2 expression was determined by Western blot. Inhibitory synaptic function was evaluated by patch clamp in lamina II neurons.

Background: Pulsed radiofrequency (PRF) treatment offers pain relief for patients suffering from chronic pain who do not respond well to conventional treatments. We tested whether PRF treatment attenuated complete Freund's adjuvant (CFA)-induced inflammatory pain. Epigenetic modification of potassium-chloride cotransporter 2 (KCC2) gene expression was examined to elucidate the potential contributing mechanism.

Results: KCC2 gene expression was suppressed through histone hypoacetylation, resulting in decreased efficacy of GABAergic signaling in CFA rats. PRF increased histone acetylation and KCC2 expression, partially restored the GABA synaptic function, and relieved sensitized pain behavior.

Conclusion: These findings suggest that PRF might be an alternative therapy for inflammatory pain. One of the underlying mechanisms is through modification of KCC2, which is an important determinant for the efficacy of inhibitory neurotransmission in the spinal cord, and its expression levels are regulated by histone acetylation epigenetically following inflammation.

Original languageEnglish
Pages (from-to)807-813
Number of pages7
JournalPain Medicine (United States)
Issue number4
StatePublished - 01 04 2017

Bibliographical note

Publisher Copyright:
© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com


  • Inflammation
  • Pain Management
  • Persistent Pain
  • Radiofrequency
  • Spinal Cord


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