LIFU Alleviates Neuropathic Pain by Improving the KCC2 Expression and Inhibiting the CaMKIV–KCC2 Pathway in the L4–L5 Section of the Spinal Cord
Ye-Hui Liao, Bin Wang, Mo-Xian Chen, Yao Liu, Li-Juan Ao
Neural Plasticity 2021, 2021, 1-10 · 10.1155/2021/6659668
Abstract
Effective treatment remains lacking for neuropathic pain (NP), a type of intractable pain. Low-intensity focused ultrasound (LIFU), a noninvasive, cutting-edge neuromodulation technique, can effectively enhance inhibition of the central nervous system (CNS) and reduce neuronal excitability. We investigated the effect of LIFU on NP and on the expression of potassium chloride cotransporter 2 (KCC 2 ) in the spinal cords of rats with peripheral nerve injury (PNI) in the lumbar 4-lumbar 5 (L4-L5) section. In this study, rats received PNI surgery on their right lower legs followed by LIFU stimulation of the L4-L5 section of the spinal cord for 4 weeks, starting 3 days after surgery. We used the 50% paw withdraw threshold (PWT 50 ) to evaluate mechanical allodynia. Western blotting (WB) and immunofluorescence (IF) were used to calculate the expression of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), calcium/calmodulin-dependent protein kinase type IV (CaMKIV), phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB), and KCC 2 in the L4-L5 portion of the spinal cord after the last behavioral tests. We found that PWT 50 decreased ( P - and LIFU + groups and increased ( P P 2 increased ( P P > 0.05) was unaffected. Our study showed that LIFU could effectively alleviate NP behavior in rats with PNI by increasing the expression of KCC 2 on spinal dorsal corner neurons. A possible explanation is that LIFU could inhibit the activation of the CaMKIV-KCC 2 pathway.
Abstract via europepmc.
Exposures
Exposure 1: LIFU stimulation of the L4-L5 spinal cord in peripheral-nerve-injury rats
Target: lumbar spinal cord — “L4-L5 section of the spinal cord”
Device: not reported
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 4,000 | ✓✓✓ |
| Pulse duration (ms) | not reportedimplied by duty cycle ÷ PRF: 0.25 ms (not stated by the paper) | |
| Pulse repetition frequency (Hz) | 800 | ✓✓✓ |
| Duty cycle (%) | 20 | ✓✓✓ |
| Sonication duration (s) | 1,200 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Pressure, domain unspecified (kPa) | 650 | ✓✓✓⚑ |
Parameters were as follows: sine pulse wave frequency, 4 MHz; duty cycle (DC), 20%; pulse repetition frequency (PRF), 0.8 KHz; irradiation intensity, 0.65 MPa; and treatment duration, 20 min/d for 4 weeks. LIFU stimulation was started on the third day after PNI surgery during the time range of 09:00-15:00.
Flags from extraction
exposures[0].unspecified_domain.pressure_kpa— The paper labels this value 'irradiation intensity' but gives it in MPa (a pressure unit, not W/cm2); recorded as a pressure value with this unit/label mismatch flagged. Domain (free field vs in situ) is not stated, so placed in unspecified_domain.timing.pulse_duration_ms— Only duty cycle (20%) and PRF (0.8 kHz) are stated; pulse duration would require arithmetic and is not given directly, so left not_reported.timing.sonication_duration_s— The paper gives 'treatment duration, 20 min/d' as a single daily continuous pulsed exposure; recorded as 1200 s under the assumption this is one uninterrupted sonication session rather than multiple discrete trains, since no separate train/inter-train structure is described.n_sessions_per_subject— Treatment is described as daily for 4 weeks but no explicit total session count is stated.