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Rapid and Delayed Effects of Pulsed Radiofrequency on Neuropathic Pain: Electrophysiological, Molecular, and Behavioral Evidence Supporting Long-Term Depression.
Pain Physician. 2017 02; 20(2):E269-E283.PP

Abstract

BACKGROUND

Pulsed radiofrequency (PRF) has been widely employed for ameliorating clinical neuropathic pain. How PRF alters electrophysiological transmission and modulates biomolecular functions in neural tissues has yet to be clarified. We previously demonstrated that an early application of low-voltage bipolar PRF adjacent to the dorsal root ganglion (DRG) reduced acute neuropathic pain in animals. By contrast, the present study investigated how PRF alters postsynaptic sensitization to produce early and delayed effects on neuropathic pain.

OBJECTIVES

Our objective was to test the hypothesis that a 5-minute session of PRF could rapidly produce selective long-term depression (LTD) on C-fiber-mediated spinal sensitization and sustain the effect through the long-lasting inhibition of injury-induced ERK-MAPK activation. This may explain the prolonged analgesic effect of PRF on chronic neuropathic pain.

STUDY DESIGN

Experiments were conducted on both normal rats and neuropathic pain rats that received spinal nerve ligation (SNL) 8 days prior.

SETTING

An animal laboratory in a medical center of a university in Taiwan.

METHODS

We first compared changes in field potentials in the L5 superficial spinal dorsal horn (SDH) that were evoked by conditioning electrical stimuli in the sciatic nerve in male adult rats before (as the baseline) and after PRF stimulation for at least 2 hours. Bipolar PRF was applied adjacent to the L5 DRG at an intensity of 5 V for 5 minutes, whereas the control rats were treated with sham applications. The electrophysiological findings were tested for any correlation with induction of spinal phospho-ERK (p-ERK) in normal and neuropathic pain rats. We then investigated the delayed effect of PRF on SNL-maintained pain behaviors for 2 weeks as well as p-ERK in SDH among the control, SNL, and PRF groups. Finally, potential injury in the DRGs after PRF stimulation was evaluated through behavioral observations and ATF-3, a neuronal stress marker.

RESULTS

In the evoked field-potential study, the recordings mediated through A- and C-afferent fibers were identified as A-component and C-component, respectively. PRF significantly reduced the C-components over 2 hours in both the normal and SNL rats, but it did not affect the A-components. In the SNL rats, the C-component was significantly depressed in the PRF group compared with the sham group. PRF also inhibited acute p-ERK induced by mechanical nociception in both the control and SNL rats. For a longer period, PRF ameliorated SNL-maintained mechanical allodynia for 10 days and thermal analgesia for 14 days, and it significantly reduced late ERK activation within spinal neurons and astrocytes 14 days afterward. Moreover, PRF in the normal rats did not alter basal withdrawal thresholds or increase the expression and distribution of ATF-3 in the DRGs.

LIMITATIONS

Several issues should be considered before translating the animal results to clinical applications.

CONCLUSIONS

Low-voltage bipolar PRF produces LTD through selective suppression on the C-component, but not on the A-component. It also inhibits ERK activation within neurons and astrocytes in SDHs. The findings suggest that PRF alleviates long-lasting neuropathic pain by selectively and persistently modulating C-fiber-mediated spinal nociceptive hypersensitivity.Key words: Pulsed radiofrequency (PRF), dorsal root ganglion (DRG), neuropathic pain, ERK activation, evoked field potential, ATF-3, long-term depression (LTD), spinal nerve ligation (SNL).

Authors+Show Affiliations

Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.Central lab, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.Department of Anesthesiology, School of Medicine, China Medical University, Taichung, Taiwan.Institute of Zoology, National Taipei University, Taipei, Taiwan.Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.Department of Anesthesiology, School of Medicine, China Medical University, Taichung, Taiwan; Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan; Pain Center, Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan; Acupuncture Research Center, China Medical University, Taichung, Taiwan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28158164

Citation

Huang, Ren-Yu, et al. "Rapid and Delayed Effects of Pulsed Radiofrequency On Neuropathic Pain: Electrophysiological, Molecular, and Behavioral Evidence Supporting Long-Term Depression." Pain Physician, vol. 20, no. 2, 2017, pp. E269-E283.
Huang RY, Liao CC, Tsai SY, et al. Rapid and Delayed Effects of Pulsed Radiofrequency on Neuropathic Pain: Electrophysiological, Molecular, and Behavioral Evidence Supporting Long-Term Depression. Pain Physician. 2017;20(2):E269-E283.
Huang, R. Y., Liao, C. C., Tsai, S. Y., Yen, C. T., Lin, C. W., Chen, T. C., Lin, W. T., Chang, C. H., & Wen, Y. R. (2017). Rapid and Delayed Effects of Pulsed Radiofrequency on Neuropathic Pain: Electrophysiological, Molecular, and Behavioral Evidence Supporting Long-Term Depression. Pain Physician, 20(2), E269-E283.
Huang RY, et al. Rapid and Delayed Effects of Pulsed Radiofrequency On Neuropathic Pain: Electrophysiological, Molecular, and Behavioral Evidence Supporting Long-Term Depression. Pain Physician. 2017;20(2):E269-E283. PubMed PMID: 28158164.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rapid and Delayed Effects of Pulsed Radiofrequency on Neuropathic Pain: Electrophysiological, Molecular, and Behavioral Evidence Supporting Long-Term Depression. AU - Huang,Ren-Yu, AU - Liao,Chia-Chi, AU - Tsai,Shih-Ying, AU - Yen,Chen-Tung, AU - Lin,Chii-Wann, AU - Chen,Tsung-Chi, AU - Lin,Wei-Tso, AU - Chang,Chi-Heng, AU - Wen,Yeong-Ray, PY - 2017/2/4/entrez PY - 2017/2/6/pubmed PY - 2017/7/18/medline SP - E269 EP - E283 JF - Pain physician JO - Pain Physician VL - 20 IS - 2 N2 - BACKGROUND: Pulsed radiofrequency (PRF) has been widely employed for ameliorating clinical neuropathic pain. How PRF alters electrophysiological transmission and modulates biomolecular functions in neural tissues has yet to be clarified. We previously demonstrated that an early application of low-voltage bipolar PRF adjacent to the dorsal root ganglion (DRG) reduced acute neuropathic pain in animals. By contrast, the present study investigated how PRF alters postsynaptic sensitization to produce early and delayed effects on neuropathic pain. OBJECTIVES: Our objective was to test the hypothesis that a 5-minute session of PRF could rapidly produce selective long-term depression (LTD) on C-fiber-mediated spinal sensitization and sustain the effect through the long-lasting inhibition of injury-induced ERK-MAPK activation. This may explain the prolonged analgesic effect of PRF on chronic neuropathic pain. STUDY DESIGN: Experiments were conducted on both normal rats and neuropathic pain rats that received spinal nerve ligation (SNL) 8 days prior. SETTING: An animal laboratory in a medical center of a university in Taiwan. METHODS: We first compared changes in field potentials in the L5 superficial spinal dorsal horn (SDH) that were evoked by conditioning electrical stimuli in the sciatic nerve in male adult rats before (as the baseline) and after PRF stimulation for at least 2 hours. Bipolar PRF was applied adjacent to the L5 DRG at an intensity of 5 V for 5 minutes, whereas the control rats were treated with sham applications. The electrophysiological findings were tested for any correlation with induction of spinal phospho-ERK (p-ERK) in normal and neuropathic pain rats. We then investigated the delayed effect of PRF on SNL-maintained pain behaviors for 2 weeks as well as p-ERK in SDH among the control, SNL, and PRF groups. Finally, potential injury in the DRGs after PRF stimulation was evaluated through behavioral observations and ATF-3, a neuronal stress marker. RESULTS: In the evoked field-potential study, the recordings mediated through A- and C-afferent fibers were identified as A-component and C-component, respectively. PRF significantly reduced the C-components over 2 hours in both the normal and SNL rats, but it did not affect the A-components. In the SNL rats, the C-component was significantly depressed in the PRF group compared with the sham group. PRF also inhibited acute p-ERK induced by mechanical nociception in both the control and SNL rats. For a longer period, PRF ameliorated SNL-maintained mechanical allodynia for 10 days and thermal analgesia for 14 days, and it significantly reduced late ERK activation within spinal neurons and astrocytes 14 days afterward. Moreover, PRF in the normal rats did not alter basal withdrawal thresholds or increase the expression and distribution of ATF-3 in the DRGs. LIMITATIONS: Several issues should be considered before translating the animal results to clinical applications. CONCLUSIONS: Low-voltage bipolar PRF produces LTD through selective suppression on the C-component, but not on the A-component. It also inhibits ERK activation within neurons and astrocytes in SDHs. The findings suggest that PRF alleviates long-lasting neuropathic pain by selectively and persistently modulating C-fiber-mediated spinal nociceptive hypersensitivity.Key words: Pulsed radiofrequency (PRF), dorsal root ganglion (DRG), neuropathic pain, ERK activation, evoked field potential, ATF-3, long-term depression (LTD), spinal nerve ligation (SNL). SN - 2150-1149 UR - https://www.unboundmedicine.com/medline/citation/28158164/Rapid_and_Delayed_Effects_of_Pulsed_Radiofrequency_on_Neuropathic_Pain:_Electrophysiological_Molecular_and_Behavioral_Evidence_Supporting_Long_Term_Depression_ L2 - http://www.painphysicianjournal.com/linkout?issn=1533-3159&vol=20&page=E269 DB - PRIME DP - Unbound Medicine ER -