Rapid and Delayed Effects of Pulsed Radiofrequency on Neuropathic Pain: Electrophysiological, Molecular, and Behavioral Evidence Supporting Long-Term Depression

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 applicationsConclusion: 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)

Efficacy of Long-Term Spinal Nerve Posterior Ramus Pulsed Radiofrequency in Treating Subacute Herpetic Neuralgia: A Prospective Randomized Controlled Trial

“…reported that long-term PRF treatment in mice triggered the recovery of resinoid-induced mechanical pain by inhibiting extracellular signal-regulated kinase (ERK). Ren Yu et al [38]. observed that PRF alleviated persistent neuropathic pain by selectively inhibiting the generation of long-term depression, inhibiting the activation of ERK in neurons and astrocytes in the superficial dorsal horn, and selectively and continuously regulating C fiber-mediated spinal cord nociceptive hypersensitivity.…”

Ultrasound-guided pulsed radiofrequency for neuromyelitis optica spectrum disorder-associated neuropathic pain: A case report

“…[15,16,21,22] The exact analgesic mechanism of PRF remains unclear. At present, it is hypothesized that an electromagnetic field is generated around the target nerve, thus activating pain inhibitory pathways, reducing norepinephrine and 5-hydroxytryptamine, [23] inhibiting the activity of excitatory nociceptive C-fibers, [24,25] reducing the release of excitatory amino acids such as glutamate, [26] inhibiting pro-inflammatory cytokines, [27,28] activating dorsal horn pain-processing neurons, [29] and reducing microglial activation. [30] It is well known that PRF is effective in relieving peripheral NP, such as postherpetic neuralgia, carpal tunnel syndrome, occipital neuralgia, etc.…”

Novel Pulsed Ultrahigh-frequency Spinal Cord Stimulation Inhibits Mechanical Hypersensitivity and Brain Neuronal Activity in Rats after Nerve Injury

“…1E) for 5, 10, or 20 min in different groups based on our previous study. 25 The animals were given 1 week to recover postsurgery. Correct SCS device implantation was ensured by at least once weekly impedance tests to confirm optimal current conductivity.…”

“…4B): A-components (10 to 220 ms, including Aβ and Aδ fiber-mediated transmission) and C-components (220 to 1,010 ms, C fiber-mediated transmission). 25,[30][31][32] Under stable anesthesia, baseline local field potentials in the primary somatosensory and anterior cingulate cortices were quiescent (fig. 4A).…”