This study demonstrates that PRF adjacent to the DRG induces an allodynia reversal in an animal model of neuropathic pain. Even though its maintenance effect is difficult to determine because of the natural recovery of the SNL model, effect-size comparison data support that PRF induces a greater allodynia recovery than sham treatment.
These findings are complementary to data published by Ozsoylar et al.27 or Aksu et al.,32 who found significant reductions in nociception after PRF application to the rear paw of SNL rats, or to the L5-6 dorsal roots of a rabbit tight sciatic nerve ligation model, respectively. In our experience, tactile allodynia is the best modality for behavioral testing in the SNL model, whereas the consistency with thermal hyperalgesia testing is less robust. Nevertheless, inclusion of other behavioral testing modalities in pain models is also recommended in future experiments. Because spontaneous,36 enhanced37 DRG activities, and sustained ectopic DRG neuron firing38 are the main causes of radicular pain, DRG is likely the most important target to limit ectopic impulse generation in patients with radicular pain. Thus, the allodynia reversal effect of PRF may be applicable to both radicular pain as well as peripheral neuropathic pain because both animal models produce similar allodynic outcomes.39 However, because mechanisms underlying pain states may differ based on etiologies, studying the effects of DRG-adjacent PRF in other pain models will assist in the determination of clinical selection criteria.
We targeted the L5 DRG in this study assuming that injured DRG is the source of injury signals to the central nervous system that leads to central sensitization. Because of L5 tight ligation and fiber degeneration, intact L4 fibers, through the sciatic nerve, may be the major pathway to carry action potentials to the central nervous system. It is possible, however, that non-noxious sensory signal propagated through intact L4 fibers can still trigger behavioral hypersensitivity by activating the sensitized L5 sensory circuit through projection neurons and their collateralization directly or through interneurons indirectly at the dorsal horn level. An experimental PRF design comparing the modulation effects of both L4 DRG and L5 DRG in pain state relief in a larger group of animals may be warranted in future experiments.
Although it is not practical to compare the magnitude and duration of antiallodynia effects of PRF in humans and animal models, our data support that PRF-induced antiallodynic effects occur approximately 1 week after PRF treatment and last for the duration of SNL-induced allodynia. However, humans may report analgesia after PRF within the first hour of treatment. This discrepancy might reflect the fact that analgesia and tactile allodynia reversal are not synonymous. Early PRF-induced analgesia may reflect that changes in local factors, such as pain modulators at the PRF site, or central factors, such as the release of endogenous endorphins, could have a role in the perception of pain relief, which was not tested in this animal model. Later allodynia reversal may reflect long-term changes in gene expression, resulting in more permanent changes in sensory neuron excitability. In fact, many investigators recommend DRG targeting for this reason, although other reasons are also cited.12
The mechanism of action of PRF is still being investigated. Findings from several studies support that PRF-induced changes seem reversible and do not rely on thermal injury. After exposing rat DRG or sciatic nerve to PRF, RF, and conductive heat, Podhajsky et al.40 reported that PRF caused transient minor structural changes, fibroblast activation, and collagen deposition. In contrast, thermal RF lesions cause nerve fiber Wallerian degeneration. Data from similar studies evaluating short-term PRF effects (1 hour) on rat DRG41 and long-term PRF effects (21 days) on the sciatic nerve42 showed that unmyelinated nerve fibers were macroscopically normal in both studies. Myelinated axons, however, showed severe nerve degeneration post-RF,42 but only a separation in the sciatic nerve,42 and interrupted myelin coverage in DRG41 post-PRF.
Erdine et al.43 showed that PRF exposure results in injuries relatively selective to small fibers (C fiber and A-δ fiber) with changes in the morphology of mitochondrial membranes, disruption and disorganization of microfilaments within the axons, and presumably microscopic changes in the axon membrane, such as changes in ion channels or pumps. It seems that PRF electrical and current fields better penetrate the axonal cell membranes of the C and A-δ fibers, causing greater disruption to inner structures. The authors suggest that damages to mitochondria via their membrane fragility causes an interruption in the essential adenosine triphosphate–mediated cellular functions and in cellular metabolism that may impede the generation of pain signals; the damage to microtubules and microfilaments may similarly impede the transmission of pain impulses.
Various studies have noted changes in dorsal horn neuronal activity, and increased cellular stress in small- and medium-caliber neurons in response to PRF at or near the DRG.41,44–46 Application of PRF, but not conventional RF, to the DRG results in an increase in c-fos immunoreactive neurons in the superficial laminae of the dorsal horn 3 hours later, suggesting a heat-independent activation of dorsal horn neurons.46 Van Zundert et al.44 reported an increase in c-fos immunoreactive cells in the dorsal horn 7 days after application of both RF and PRF to the cervical dorsal root, representing a late neuronal activation. In addition, Hamann et al.45 revealed an upregulation of ATF3 in DRG neurons, but not in the sciatic nerve, both of which were subjected to PRF, suggesting that the biological response to PRF is tissue or cell-type specific and independent from thermal damages.45 Because both c-fos and ATF3 are transcription factors, these findings support that PRF pain relief may derive from long-term modulation of cell functions by altering gene expression, which may include positive PRF effects on synaptic strength and long-term enhancement,47 which is related to central sensitization, a major player in chronic pain development.48
In this study, PRF was applied similar to clinical variables. The voltage was limited to 25 V to avoid a thermal ablation (temperature limited to 42°C) as the other variables (500-kHz pulses, 20 milliseconds in duration, rate of 2 Hz, period of 120 seconds) were fixed for smaller rat DRG. Even though 25-V output is not the mode in clinical practice, it is occasionally cited.6 However, animal studies that vary technical considerations, such as ideal voltage, number of cycles, pulse duration, and optimal electrode distance, are also encouraged and will refine the application of PRF in pain treatment. Furthermore, we used an open procedure to ensure reliable DRG-adjacent PRF application because the anesthetized animal cannot report vibration, buzzing, pressure, or tingling sensation for probe placement as humans do. However, this invasive approach will not be necessary in clinical practice because PRF adjacent to the DRG can be performed percutaneously via fluoroscopic guidance. Finally, although it did not affect allodynia recovery in the sham rats, the application of electrocautery, in combination with direct pressure, for bleeding control may cause unnecessary electrical energy at the PRF site, which should be avoided in future studies if possible.
In conclusion, PRF is effective for the treatment of experimental neuropathic pain via DRG modulation. Further elucidation of exact mechanisms underlying PRF-induced DRG modulation in pain state relief, however, is needed.
Name: Danielle M. Perret, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Danielle M. Perret has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Doo-Sik Kim, MD, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Doo-Sik Kim has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Kang-Wu Li, MD, PhD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Kang-Wu Li has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Karin Sinavsky, MD, MS.
Contribution: This author helped write the manuscript.
Attestation: Karin Sinavsky has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Robert L. Newcomb, PhD.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Robert L. Newcomb has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Jason M. Miller, MD.
Contribution: This author helped design the study, conduct the study, and analyze the data.
Attestation: Jason M. Miller has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Z. David Luo, MD, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Z. David Luo has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
The authors thank Mr. Joshua Lee for his technical assistance during the preparation of the manuscript.
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