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 (KCC2) 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 (PWT50) 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 KCC2 in the L4–L5 portion of the spinal cord after the last behavioral tests. We found that PWT50 decreased (P < 0.05) 3 days post-PNI surgery in the LIFU− and LIFU+ groups and increased (P < 0.05) after 4 weeks of LIFU stimulation. The expression of p-CREB and CaMKIV decreased (P < 0.05) and that of KCC2 increased (P < 0.05) after 4 weeks of LIFU stimulation, but that of p-ERK1/2 (P > 0.05) was unaffected. Our study showed that LIFU could effectively alleviate NP behavior in rats with PNI by increasing the expression of KCC2 on spinal dorsal corner neurons. A possible explanation is that LIFU could inhibit the activation of the CaMKIV–KCC2 pathway.
Highlights
Neuropathic pain (NP) is defined as pain originating from primary lesions and dysfunction of the somatosensory system, either at the peripheral or central level [1]
An increasing amount of evidence has shown that downregulation of potassium chloride cotransporter 2 (KCC2) in the spinal cord plays an important role in NP
It plays a prominent role in maintaining low [Cl−]i, which is necessary for the function of GABAA and glycine receptors (GlyRs) and for mediating spinal cord inhibition [8, 10]
Summary
Neuropathic pain (NP) is defined as pain originating from primary lesions and dysfunction of the somatosensory system, either at the peripheral or central level [1]. As a refractory and chronic pain that can manifest in various ways, including as chronic low back pain or sciatica, NP is a severe problem. It affects 6.9%–10% of the population worldwide and seriously diminishes patient’s quality of life [2], increasing the economic burden on the patient’s family and on society [4,5,6]. After peripheral nerve injury (PNI), the expression of KCC2 on the neuronal membrane is downregulated, and the concentration of Cl− ([Cl−]i) in nerve cells is upregulated, thereby reducing the inhibitory effect of the neurotransmitter γ-aminobutyric acid (GABA) [8,9,10].
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