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



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.



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.



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.
Department of Anesthesiology, Chang Gung Memorial Hospital-Kaohsiung Medical Centre, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Chia-Kai
CK
Liu
Department of Anesthesiology, Chia-Yi Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Chia-Yi, Taiwan.
Wen-Tzu
WT
Liao
Department of Anesthesiology, Chang Gung Memorial Hospital-Kaohsiung Medical Centre, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Yu-Chi
YC
Chu
Department of Anesthesiology, Chang Gung Memorial Hospital-Kaohsiung Medical Centre, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Chien-Hui
CH
Yang
Department of Anesthesiology, Chang Gung Memorial Hospital-Kaohsiung Medical Centre, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Kuan-Hung
KH
Chen
Department of Anesthesiology, Chang Gung Memorial Hospital-Kaohsiung Medical Centre, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Chih-Hsien
CH
Wu
Department of Anesthesiology, Chang Gung Memorial Hospital-Kaohsiung Medical Centre, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Chung-Ren
CR
Lin
D000818:Animals; D059350:Chronic Pain / Q000139:chemically induced / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D011189:Potassium Chloride / Q000378:metabolism; D061208:Pulsed Radiofrequency Treatment / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism*; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D000096922:K Cl- Cotransporters
D005620:Freund's Adjuvant; D011189:Potassium Chloride; D027981:Symporters; D000096922:K Cl- Cotransporters
Inflammation; Pain Management; Persistent Pain; Radiofrequency; Spinal Cord