Association between extracellular signal-regulated kinase expression and the anti-allodynic effect in rats with spared nerve injury by applying immediate pulsed radiofrequency

Abstract

BackgroundThe application of pulsed radiofrequency (PRF) close to the dorsal root ganglia, or peripheral nerves, has been demonstrated to be effective for the treatment of chronic neuropathic pain conditions. The goal of this study was to investigate the analgesic effect of immediate PRF treatment after nerve injury and its possible cellular alterations in the dorsal horn of the spinal cord in rats with spared nerve injury (SNI).MethodsNeuropathic pain was achieved in a SNI neuropathic pain model by ligating and cutting the common peroneal and tibial branches of the left sciatic nerve, leaving the sural nerve intact. Wistar rats were divided into four groups that received different treatments, i.e., SNI and PRF for 6 min at 45 V (SNI + PRF-45 V), at 60 V (SNI + PRF-60 V), SNI alone, and sham groups. After the SNI surgery, each rat was immediately given the PRF treatment (500 kHz, rate of 2 Hz, 20 ms duration, temperature below 42 °C) on the left sciatic nerve 0.3–0.4 cm proximal to the injured site. The behavioral measurements included mechanical allodynia and cold allodynia of the ipsilateral hind paw and were performed during the 28 days that followed the SNI surgery and PRF treatment. Total extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phospho-ERK1/2 were measured using Western blot in the ipsilateral spinal cord from animals in the different groups.ResultsThe three groups of rats with nerve injuries manifested a lower paw withdrawal threshold (PWT) in the behavioral measurement of mechanical allodynia and a shorter painful-behavior duration in the cold allodynia test over 28 days. Mechanical allodynia measurement showed that both the PRF-45 V and PRF-60 V treatment groups exhibited a more prominent antiallodynic effect than did the SNI group from days 1 to 28 after surgery. Similarly, in comparison with the SNI group, both the SNI + PRF-45 V and SNI + PRF-60 V groups had significant inhibition on the cold allodynia measurement from days 1 to 28 after surgery. Furthermore, the activation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the ipsilateral spinal dorsal horn of SNI rats was effectively inhibited in the SNI + PRF-45 V and SNI + PRF-60 V groups for 28 days after surgery.ConclusionsImmediate PRF application on the proximal nerve injury site provided a significant inhibition of neuropathic pain formation, accompanied by the inhibition of ERK activation.

Long-Term Anti-Allodynic Effect of Immediate Pulsed Radiofrequency Modulation through Down-Regulation of Insulin-Like Growth Factor 2 in a Neuropathic Pain Model

“…As listed in Table 1 , four enriched GO terms (extra-cellular matrix, extra-cellular region part, extra-cellular region, and extra-cellular matrix part) were filtered according to Parent–Child–Union—Bonferroni criteria (adjusted p < 0.001). Three genes (for Ckm , RGD1591759 , and Igf2 ) were selected from the 80 genes mentioned because of their relationships with ERK and mitogen-activated protein kinase (MAPK) pathways found using an online GO database [ 18 ]. Among them, IGF2 was chosen as our target, because IGF2 was the only one molecule that was acquired by cross-matching the two databases.…”

“…To establish whether the repression of IGF2 plays a role in PRF-induced anti-allodynic effects, we analyzed the expression of IGF2 in the left L4–L6 dorsal horns of rats under different treatments (SNI alone and SNI + immPRF). Meanwhile, we used the phosphorylated ERK1/2 in response to the nerve injury to evaluate allodynia as described by others [ 17 , 18 ]. Figure 4 A shows the immunofluorescent images of IGF2 and phosphorylated ERK1/2 immunoreactivity on sections taken from the left dorsal horn region of rats with different treatments on Day 21.…”

“…Low-voltage PRF may attenuate mechanical allodynia and thermal hyperalgesia in a rat model of neuropathic pain produced by spinal nerve ligation (SNL) by affecting the phosphorylation of ERK [ 17 ]. Immediate PRF application to sites proximal to nerve injury significantly inhibited the development of neuropathic pain, accompanied by inhibited ERK activation in rats after spared nerve injury (SNI) [ 18 ]. Therefore, the inhibition of ERK activation might be a novel target for the treatment of neuropathic pain [ 19 , 20 , 21 ].…”

“…Various durations of anti-allodynia effects have been observed following PRF application after nerve injury, but most PRF applications were applied a considerable time after the development of neuropathic pain [ 22 , 23 , 24 ]. We were among the first to apply PRF immediately to alleviate SNI-induced neuropathic pain and found that immediate PRF of 60 V for 6 min had anti-nociceptive effects for up to 28 days [ 18 ].…”

Looking ahead: chronic spinal pain management

“…In addition, the emerging biology of pulsed radiofrequency neurotomies is unique in that it provides pain relief without causing significant damage to nervous tissue, with animal studies demonstrating modulation of pain transmission in the spinal nerves and spinal cord by a range of mechanisms including modulating gene expression 19 and microglial neurotransmitters. 20 – 22 These emerging concepts in the literature start to provide biological mechanisms to the use of pulsed radiofrequency modalities for people with spinal pain.…”