Expression and effect of sodium-potassium-chloride cotransporter on dorsal root ganglion neurons in a rat model of chronic constriction injury

Tan, Chao‐Yang; Wang, Yanping; Han, Yuanyuan; Lu, Bi-Han; Ji, Wei; Zhu, Li; Wang, Yan; Shi, Wen‐Yan; Shan, Liya; Zhang, Liang; Ma, Ketao; Li, Li; Si, Jun‐Qiang

doi:10.4103/1673-5374.268904

Cited by 13 publications

(8 citation statements)

References 38 publications

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“…At the functional level, the intracellular chloride concentration was detected by chloride fluorescent probe technology to verify that capsaicin phosphorylates NKCC1 transporter through the PKC/ERK pathway and activates its function ( Tan et al, 2020 ). Meanwhile, the fluorescence intensity of chloride ion decreases proportionally according to the increase of intracellular chloride ion concentration.…”

Section: Resultsmentioning

confidence: 99%

“…The GABA released by intermediate inhibitory neurons activates GABA A receptors, opens Cl – channels, and increases Cl – efflux (inward current increase), as shown in Figures 3C,D . Thus, the membrane potential of the presynaptic membrane at the central end of the primary sensory end undergoes a sharp, excessive depolarization and reaches the threshold potential to trigger the AP, which could cause DRR pain sensitivity ( Tan et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…The method was adopted from the authors’ laboratory ( Tan et al, 2020 ). After the anesthetized rats were sacrificed, the L 4 – 6 segment spine was taken and placed in extracellular fluid saturated with oxygen (150 mmol/l NaCl, 5 mmol/l KCl, 1 mmol/l MgCl 2 , 10 mmol/l HEPES, 10 mmol/l D-glucose, 20 mmol/l sucrose, and 3.32 mmol/l CaCl 2 ; 7.2–7.4 pH; osmotic pressure of 320–350 mOsm).…”

Section: Methodsmentioning

confidence: 99%

“…L 4 – 6 DRG specimens were collected from different groups. In accordance with the experimental procedure of Batti et al (2013) and the improvement methods from the authors’ laboratory ( Tan et al, 2020 ), the animals were sacrificed using 4% sevoflurane, with immediate stripping of L 4 – 6 DRG. Then, samples were cut with eye scissors, subjected to enzyme digestion, and centrifuged.…”

Section: Methodsmentioning

confidence: 99%

“…Studies have found that an increase in sodium, potassium, and chloride co-transporter (NKCC1) in the DRG could trigger pain in a neuropathic pain model in rats. It may also increase the concentration of intracellular chlorine ions, thereby triggering dorsal root reflex (DRR) ( Tan et al, 2020 ). Therefore, regulating the expression of NKCC1 may be another direction for the treatment of pain.…”

Section: Introductionmentioning

confidence: 99%

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Improving NKCC1 Function Increases the Excitability of DRG Neurons Exacerbating Pain Induced After TRPV1 Activation of Primary Sensory Neurons

Deng

Tang

Chang

et al. 2021

Front. Cell. Neurosci.

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Background Our aim was to investigate the effects of the protein expression and the function of sodium, potassium, and chloride co-transporter (NKCC1) in the dorsal root ganglion (DRG) after activation of transient receptor potential vanilloid 1 receptor (TRPV1) in capsaicin-induced acute inflammatory pain and the possible mechanism of action.Methods Male Sprague–Dawley rats were randomly divided into control, capsaicin, and inhibitor groups. The expression and distribution of TRPV1 and NKCC1 in rat DRG were observed by immunofluorescence. Thermal radiation and acetone test were used to detect the pain threshold of heat and cold noxious stimulation in each group. The expressions of NKCC1 mRNA, NKCC1 protein, and p-NKCC1 in the DRG were detected by PCR and western blotting (WB). Patch clamp and chloride fluorescent probe were used to observe the changes of GABA activation current and intracellular chloride concentration. After intrathecal injection of protein kinase C (PKC) inhibitor (GF109203X) or MEK/extracellular signal-regulated kinase (ERK) inhibitor (U0126), the behavioral changes and the expression of NKCC1 and p-ERK protein in L4–6 DRG were observed.Result: TRPV1 and NKCC1 were co-expressed in the DRG. Compared with the control group, the immunofluorescence intensity of NKCC1 and p-NKCC1 in the capsaicin group was significantly higher, and the expression of NKCC1 in the nuclear membrane was significantly higher than that in the control group. The expression of NKCC1 mRNA and protein of NKCC1 and p-NKCC1 in the capsaicin group were higher than those in the control group. After capsaicin injection, GF109203X inhibited the protein expression of NKCC1 and p-ERK, while U0126 inhibited the protein expression of NKCC1. In the capsaicin group, paw withdrawal thermal latency (WTL) was decreased, while cold withdrawal latency (CWL) was prolonged. Bumetanide, GF109203X, or U0126 could reverse the effect. GABA activation current significantly increased in the DRG cells of the capsaicin group, which could be reversed by bumetanide. The concentration of chloride in the DRG cells of the capsaicin group increased, but decreased after bumetanide, GF109203X, and U0126 were administered.Conclusion Activation of TRPV1 by exogenous agonists can increase the expression and function of NKCC1 protein in DRG, which is mediated by activation of PKC/p-ERK signaling pathway. These results suggest that DRG NKCC1 may participate in the inflammatory pain induced by TRPV1.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Improving NKCC1 Function Increases the Excitability of DRG Neurons Exacerbating Pain Induced After TRPV1 Activation of Primary Sensory Neurons

Deng

Tang

Chang

et al. 2021

Front. Cell. Neurosci.

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The Role of TMEM16A/ERK/NK-1 Signaling in Dorsal Root Ganglia Neurons in the Development of Neuropathic Pain Induced by Spared Nerve Injury (SNI)

Chen

Kong

et al. 2021

Mol Neurobiol

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Increasing evidence suggests that transmembrane protein 16A (TMEM16A) in nociceptive neurons is an important molecular component contributing to peripheral pain transduction. The present study aimed to evaluate the role and mechanism of TMEM16A in chronic nociceptive responses elicited by spared nerve injury (SNI). In this study, SNI was used to induce neuropathic pain. Drugs were administered intrathecally. The expression and cellular localization of TMEM16A, the ERK pathway, and NK-1 in the dorsal root ganglion (DRG) were detected by western blot and immunofluorescence. Behavioral tests were used to evaluate the role of TMEM16A and p-ERK in SNI-induced persistent pain and hypersensitivity. The role of TMEM16A in the hyperexcitability of primary nociceptor neurons was assessed by electrophysiological recording. The results show that TMEM16A, p-ERK, and NK-1 are predominantly expressed in small neurons associated with nociceptive sensation. TMEM16A is colocalized with p-ERK/NK-1 in DRG. TMEM16A, the MEK/ERK pathway, and NK-1 are activated in DRG after SNI. ERK inhibitor or TMEM16A antagonist prevents SNI-induced allodynia. ERK and NK-1 are downstream of TMEM16A activation. Electrophysiological recording showed that CaCC current increases and intrathecal application of T16Ainh-A01, a selective TMEM16A inhibitor, reverses the hyperexcitability of DRG neurons harvested from rats after SNI. We conclude that TMEM16A activation in DRG leads to a positive interaction of the ERK pathway with activation of NK-1 production and is involved in the development of neuropathic pain after SNI. Also, the blockade of TMEM16A or inhibition of the downstream ERK pathway or NK-1 upregulation may prevent the development of neuropathic pain.

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Exercise as a therapeutic intervention for neuropathic pain after spinal cord injury

Houlé

Detloff

2022

Spinal Cord Injury Pain

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Expression and effect of sodium-potassium-chloride cotransporter on dorsal root ganglion neurons in a rat model of chronic constriction injury

Cited by 13 publications

References 38 publications

Improving NKCC1 Function Increases the Excitability of DRG Neurons Exacerbating Pain Induced After TRPV1 Activation of Primary Sensory Neurons

Improving NKCC1 Function Increases the Excitability of DRG Neurons Exacerbating Pain Induced After TRPV1 Activation of Primary Sensory Neurons

The Role of TMEM16A/ERK/NK-1 Signaling in Dorsal Root Ganglia Neurons in the Development of Neuropathic Pain Induced by Spared Nerve Injury (SNI)

Exercise as a therapeutic intervention for neuropathic pain after spinal cord injury

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