Long-term High-frequency Spinal Cord Stimulation (SCS) Attenuates Neuropathic Pain Through Modulating Microglia Activation And Polarization

Abstract

ntroduction: Background: High-frequency (HF) SCS has been demon-strated to be successful for treating chronic neuropathic pain. However,the mechanism of HF SCS has been unclear. Microglial cells, as a type ofimportant immune cells in the central nervous system (CNS), play animportant role in pain regulation. The research regarding its analgesiceffect on SCS is still in blank. In this study, we investigated the mechanismof microglial regulation behind the pain relief induced by HFSCS.Materials/Methods: Methodology: Male SD rats weighting 200-230gwere allocated to 4 study groups: vehicle group; sham-group; SNI group;SNI+4 days HF SCS. Neuropathic pain model was via spared nerve injury(SNI) surgery. The spinal column of the rat was exposed by a mid-line lum-bar incision followed by laminectomy at T12–T13. A custom-made4-contact electrode (0.9mm diameter; mainland company) was introducedinto the epidural space at T13 level. SCS was delivered for 60mins/4 daysbeginning 2 weeks after SNI as follows: frequency:10khz; pulse width:20μsec; amplitude: 0.4v (90% motor threshold). The paw withdraw thresh-old (PWT) was measured by von Frey test each 15min during the SCS.Western blot and immunofluorescence were used to measure the expres-sion and the cellular distribution of CD86/IL-1beta and CD206/Arg-1. Results: Results Before SNI, baseline PWT was measured. Two weeksafter SNI, all groups showed a significant decrease in their PWT ipsilaterally(p<0.05, n=6). HFSCS significantly increased the PWT of SNI+HFSCS groupat the 1st day(p<0.05,n=6)and reached the peak at the 4th day(p<0.01,n=6) compared with the sham group. The analgesic effect of SCSlasted up to 15 days since the first time SCS, and gradually returned tothe same level (p>0.05 n=6) as sham group. The expression of IL-1βincreased after the long term HFSCS (p<0.05 versus sham group) whereasthe expression of CD206 and CD86 showed an opposite trend in the SNI+HF SCS group. Furthermore, after long term HFSCS, the activation ofmicroglia was significantly reduced in the SNI+HFSCS group (p< 0.01 ver-sus the sham group).Discussion: Conclusions HFSCS increased the PWT after SNI and theanalgesia continued up to 15th days, suggesting that the long term HFSCSmay be an effective parameter in clinical. One potential mechanism forHFSCS may be to reduce glial activation, as well as changing the microgliapolarization to the M2 type at the level of the spinal cord.