Microglial BDNF, PI3K, and p-ERK in the Spinal Cord Are Suppressed by Pulsed Radiofrequency on Dorsal Root Ganglion to Ease SNI-Induced Neuropathic Pain in Rats

Abstract

Background. Pulsed radiofrequency (PRF) on the dorsal root ganglion (DRG) has been applied to alleviate neuropathic pain effectively, yet the mechanisms underlying pain reduction owing to this treatment are not clarified completely. The activated microglia, brain-derived neurotrophic factor (BDNF), phosphatidylinositol 3-kinase (PI3K), and phosphorylated extracellular signal-regulated kinase (p-ERK) in the spinal cord were demonstrated to be involved in developing neuropathic pain. Also, it has been just known that PRF on DRG inhibits the microglial activation in nerve injury rats. Here, we aim to investigate whether PRF treatment could regulate the levels of BDNF, PI3K, and p-ERK in the spinal cord of rats with spared nerve injury (SNI) via suppressing the spinal microglia activation to ease neuropathic pain. Methods. The rats with SNI were intrathecally treated with minocycline (specific microglia inhibitor) or same volume of dimethyl sulfoxide once daily, beginning from 1 h before nerve transection to 7 days. PRF was applied adjacent to the L4-L5 DRG of rats with SNI at 45 V for 6 min on the seventh postoperative day, whereas the free-PRF rats were treated without PRF. The withdrawal thresholds were studied, and the spinal levels of ionized calcium-binding adapter molecule 1 (Iba1), BDNF, PI3K, and p-ERK were calculated by western blot analysis, reverse transcription-polymerase chain reaction, and immunofluorescence. Results. The paw withdrawal mechanical threshold and paw withdrawal thermal latency decreased in the ipsilateral hind paws after SNI, and the spinal levels of Iba1, BDNF, PI3K, and p-ERK increased on day 21 after SNI compared with baseline (P<0.01). An intrathecal injection of minocycline led to the reversal of SNI-induced allodynia and increase in levels of Iba1, BDNF, PI3K, and p-ERK. Withdrawal thresholds recovered partially after a single PRF treatment for 14 days, and SNI-induced microglia hyperactivity, BDNF upregulation, and PI3K and ERK phosphorylation in the spinal cord reduced on D14 due to the PRF procedure. Conclusion. Microglial BDNF, PI3K, and p-ERK in the spinal cord are suppressed by the therapy of PRF on DRG to ease SNI-induced neuropathic pain in rats.

Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain

“…In this study, differences in gene expression for the PI3Kγ-AKT-cGMP-JNK signaling pathway (Xu et al, 2019) and morphine tolerance (Chen et al, 2018;König et al, 2010).…”

Therapeutic effects of peripherally administrated neural crest stem cells on pain and spinal cord changes after sciatic nerve transection

“…ERK and NF-κB p65 signaling pathways were activated after sciatic nerve injury, with increased protein expression, which are associated with spinal glial activation and central sensitization [25][26][27]. The double immunofluorescence labeling for c-fos and p-ERK was increased after the saphenous nerve injury and disconnection from their dominant receptive field, suggesting that the collateral synaptic input to second-order spinal dorsal horn neurons was activated [52].…”

“…However, it is not clear whether there is a therapeutic effect of NCSCs on central sensitization in the spinal cord that leads to pain relief and improved outcomes after sciatic nerve transection (SNT). While intraspinal injection of BMSCs was reported to suppress the NF-κB and p-p38 MAPK pathways in the spinal cord after spinal cord injury (SCI) [24], it is still unknown whether the ERK and NF-κB signals, which are associated with spinal glial activation and central sensitization [25][26][27], are associated with the effect of peripherally applied NCSCs. The relevant underlying mechanisms remain unelucidated.…”

<p>Application and Therapeutic Effect of Puncturing of the Costal Transverse Process for Pulsed Radiofrequency Treated T1-T3 Herpes Zoster Neuralgia</p>

“…In the SNI rat model, it was found that PRF could relieve neuropathic pain by inhibiting the overexpression of IRF8 and BDNF in the spinal cord of NAC, 24 and inhibiting the activation of spinal microglia to downregulate DNF and the phosphorylation of PI3K and ERK. 25 While in the CCI rat model, it was found that PRF can upregulate the transcription and translation of GDNF in the compressed sciatic nerve, 26 inhibit the activity of IRF8, p38 and microglia in the spinal cord of rats, 27 downregulate the expression of chain proteins, 28 and enhance the levels of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in the blood of rats, 28 and then achieve the purpose of relieving neuropathic pain.…”