scholarly journals Conserved Expression of Nav1.7 and Nav1.8 Contribute to the Spontaneous and Thermally Evoked Excitability in IL-6 and NGF-Sensitized Adult Dorsal Root Ganglion Neurons In Vitro

2020 ◽  
Vol 7 (2) ◽  
pp. 44
Author(s):  
Rahul R. Atmaramani ◽  
Bryan J. Black ◽  
June Bryan de la Peña ◽  
Zachary T. Campbell ◽  
Joseph J. Pancrazio
Keyword(s):  
Sodium Channels ◽  
Sensory Neurons ◽  
Inflammatory Pain ◽  
Dorsal Root Ganglion Neurons ◽  
Electrode Arrays ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Ganglion Neurons

Sensory neurons respond to noxious stimuli by relaying information from the periphery to the central nervous system via action potentials driven by voltage-gated sodium channels, specifically Nav1.7 and Nav1.8. These channels play a key role in the manifestation of inflammatory pain. The ability to screen compounds that modulate voltage-gated sodium channels using cell-based assays assumes that key channels present in vivo is maintained in vitro. Prior electrophysiological work in vitro utilized acutely dissociated tissues, however, maintaining this preparation for long periods is difficult. A potential alternative involves multi-electrode arrays which permit long-term measurements of neural spike activity and are well suited for assessing persistent sensitization consistent with chronic pain. Here, we demonstrate that the addition of two inflammatory mediators associated with chronic inflammatory pain, nerve growth factor (NGF) and interleukin-6 (IL-6), to adult DRG neurons increases their firing rates on multi-electrode arrays in vitro. Nav1.7 and Nav1.8 proteins are readily detected in cultured neurons and contribute to evoked activity. The blockade of both Nav1.7 and Nav1.8, has a profound impact on thermally evoked firing after treatment with IL-6 and NGF. This work underscores the utility of multi-electrode arrays for pharmacological studies of sensory neurons and may facilitate the discovery and mechanistic analyses of anti-nociceptive compounds.

scholarly journals Sodium Channel Nav1.3 Is Expressed by Polymorphonuclear Neutrophils during Mouse Heart and Kidney Ischemia InVivo and Regulates Adhesion, Transmigration, and Chemotaxis of Human and Mouse Neutrophils In Vitro

2018 ◽  
Vol 128 (6) ◽  
pp. 1151-1166 ◽  
Author(s):  
Marit Poffers ◽  
Nathalie Bühne ◽  
Christine Herzog ◽  
Anja Thorenz ◽  
Rongjun Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Polymorphonuclear Neutrophils ◽  
Human Neutrophils ◽  
Mouse Heart ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

Abstract Background Voltage-gated sodium channels generate action potentials in excitable cells, but they have also been attributed noncanonical roles in nonexcitable cells. We hypothesize that voltage-gated sodium channels play a functional role during extravasation of neutrophils. Methods Expression of voltage-gated sodium channels was analyzed by polymerase chain reaction. Distribution of Nav1.3 was determined by immunofluorescence and flow cytometry in mouse models of ischemic heart and kidney injury. Adhesion, transmigration, and chemotaxis of neutrophils to endothelial cells and collagen were investigated with voltage-gated sodium channel inhibitors and lidocaine in vitro. Sodium currents were examined with a whole cell patch clamp. Results Mouse and human neutrophils express multiple voltage-gated sodium channels. Only Nav1.3 was detected in neutrophils recruited to ischemic mouse heart (25 ± 7%, n = 14) and kidney (19 ± 2%, n = 6) in vivo. Endothelial adhesion of mouse neutrophils was reduced by tetrodotoxin (56 ± 9%, unselective Nav-inhibitor), ICA121431 (53 ± 10%), and Pterinotoxin-2 (55 ± 9%; preferential inhibitors of Nav1.3, n = 10). Tetrodotoxin (56 ± 19%), ICA121431 (62 ± 22%), and Pterinotoxin-2 (59 ± 22%) reduced transmigration of human neutrophils through endothelial cells, and also prevented chemotactic migration (n = 60, 3 × 20 cells). Lidocaine reduced neutrophil adhesion to 60 ± 9% (n = 10) and transmigration to 54 ± 8% (n = 9). The effect of lidocaine was not increased by ICA121431 or Pterinotoxin-2. Conclusions Nav1.3 is expressed in neutrophils in vivo; regulates attachment, transmigration, and chemotaxis in vitro; and may serve as a relevant target for antiinflammatory effects of lidocaine.

scholarly journals Targeted Osmotic Lysis of Highly Invasive Breast Carcinomas Using Pulsed Magnetic Field Stimulation of Voltage-Gated Sodium Channels and Pharmacological Blockade of Sodium Pumps

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1420
Author(s):  
Dennis Paul ◽  
Paul Maggi ◽  
Fabio Del Piero ◽  
Steven D. Scahill ◽  
Kelly Jean Sherman ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Electrical Current ◽  
Normal Breast ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Reduce Tumor Growth ◽  
Osmotic Lysis ◽  
Stimulation Of

Concurrent activation of voltage-gated sodium channels (VGSCs) and blockade of Na+ pumps causes a targeted osmotic lysis (TOL) of carcinomas that over-express the VGSCs. Unfortunately, electrical current bypasses tumors or tumor sections because of the variable resistance of the extracellular microenvironment. This study assesses pulsed magnetic fields (PMFs) as a potential source for activating VGSCs to initiate TOL in vitro and in vivo as PMFs are unaffected by nonconductive tissues. In vitro, PMFs (0–80 mT, 10 msec pulses, 15 pps for 10 min) combined with digoxin-lysed (500 nM) MDA-MB-231 breast cancer cells stimulus-dependently. Untreated, stimulation-only, and digoxin-only control cells did not lyse. MCF-10a normal breast cells were also unaffected. MDA-MB-231 cells did not lyse in a Na+-free buffer. In vivo, 30 min of PMF stimulation of MDA-MB-231 xenografts in J/Nu mice or 4T1 homografts in BALB/c mice, concurrently treated with 7 mg/kg digoxin reduced tumor size by 60–100%. Kidney, spleen, skin and muscle from these animals were unaffected. Stimulation-only and digoxin-only controls were similar to untreated tumors. BALB/C mice with 4T1 homografts survived significantly longer than mice in the three control groups. The data presented is evidence that the PMFs to activate VGSCs in TOL provide sufficient energy to lyse highly malignant cells in vitro and to reduce tumor growth of highly malignant grafts and improve host survival in vivo, thus supporting targeted osmotic lysis of cancer as a possible method for treating late-stage carcinomas without compromising noncancerous tissues.

Development of the 1,2,4-triazole-based anticonvulsant drug candidates acting on the voltage-gated sodium channels. Insights from in-vivo, in-vitro, and in-silico studies

2019 ◽  
Vol 129 ◽  
pp. 42-57 ◽  
Author(s):  
Barbara Kaproń ◽  
Jarogniew J. Łuszczki ◽  
Anita Płazińska ◽  
Agata Siwek ◽  
Tadeusz Karcz ◽  
...  
Keyword(s):  
Sodium Channels ◽  
In Silico ◽  
Anticonvulsant Drug ◽  
Voltage Gated ◽  
Drug Candidates ◽  
Voltage Gated Sodium Channels ◽  
In Silico Studies

scholarly journals Neuropathic Pain Develops Normally in Mice Lacking both Nav1.7 and Nav1.8

2005 ◽  
Vol 1 ◽  
pp. 1744-8069-1-24 ◽  
Author(s):  
Mohammed A Nassar ◽  
Alessandra Levato ◽  
L Caroline Stirling ◽  
John N Wood
Keyword(s):  
Neuropathic Pain ◽  
Sodium Channels ◽  
Sensory Neurons ◽  
Inflammatory Pain ◽  
Pain Thresholds ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Pain Symptoms ◽  
Α Subunits

Two voltage gated sodium channel α-subunits, Nav1.7 and Nav1.8, are expressed at high levels in nociceptor terminals and have been implicated in the development of inflammatory pain. Mis-expression of voltage-gated sodium channels by damaged sensory neurons has also been implicated in the development of neuropathic pain, but the role of Nav1.7 and Nav1.8 is uncertain. Here we show that deleting Nav1.7 has no effect on the development of neuropathic pain. Double knockouts of both Nav1.7 and Nav1.8 also develop normal levels of neuropathic pain, despite a lack of inflammatory pain symptoms and altered mechanical and thermal acute pain thresholds. These studies demonstrate that, in contrast to the highly significant role for Nav1.7 in determining inflammatory pain thresholds, the development of neuropathic pain does not require the presence of either Nav1.7 or Nav1.8 alone or in combination.

scholarly journals Modulation of Voltage-Gated Sodium Channels by Activation of Tumor Necrosis Factor Receptor-1 and Receptor-2 in Small DRG Neurons of Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
M. Leo ◽  
S. Argalski ◽  
M. Schäfers ◽  
T. Hagenacker
Keyword(s):  
Tumor Necrosis Factor ◽  
Sodium Channels ◽  
Tumor Necrosis ◽  
Dorsal Root Ganglion Neurons ◽  
Maximum Effect ◽  
Tnf Receptor ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Ganglion Neurons ◽  
Necrosis Factor

Tumor necrosis factor- (TNF-)αis a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain. Its effects are mediated by two receptors, TNF receptor-1 (TNFR-1) and TNF receptor-2 (TNFR-2). These receptors play a crucial role in the sensitization of voltage-gated sodium channels (VGSCs), a key mechanism in the pathogenesis of chronic pain. Using the whole-cell patch-clamp technique, we examined the influence of TNFR-1 and TNFR-2 on VGSCs and TTX-resistant NaV1.8 channels in isolated rat dorsal root ganglion neurons by using selective TNFR agonists. The TNFR-1 agonist R32W (10 pg/mL) caused an increase in the VGSC current (INa(V)) by 27.2 ± 5.1%, while the TNFR-2 agonist D145 (10 pg/mL) increased the current by 44.9 ± 2.6%. This effect was dose dependent. Treating isolated NaV1.8 with R32W (100 pg/mL) resulted in an increase inINaV(1.8)by 18.9 ± 1.6%, while treatment with D145 (100 pg/mL) increased the current by 14.5 ± 3.7%. Based on the current-voltage relationship, 10 pg of R32W or D145 led to an increase inINa(V)in a bell-shaped, voltage-dependent manner with a maximum effect at −30 mV. The effects of TNFR activation on VGSCs promote excitation in primary afferent neurons and this might explain the sensitization mechanisms associated with neuropathic and inflammatory pain.

scholarly journals Effects of (−)-Gallocatechin-3-Gallate on Tetrodotoxin-Resistant Voltage-Gated Sodium Channels in Rat Dorsal Root Ganglion Neurons

2013 ◽  
Vol 14 (5) ◽  
pp. 9779-9789 ◽  
Author(s):  
Yan Zhang ◽  
Yan-Yan Jia ◽  
Jin-Lei Guo ◽  
Pei-Qing Liu ◽  
Jian-Min Jiang
Keyword(s):  
Dorsal Root Ganglion ◽  
Sodium Channels ◽  
Dorsal Root ◽  
Dorsal Root Ganglion Neurons ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Ganglion Neurons

TNF-α enhances the currents of voltage gated sodium channels in uninjured dorsal root ganglion neurons following motor nerve injury

2011 ◽  
Vol 227 (2) ◽  
pp. 279-286 ◽  
Author(s):  
Xi Chen ◽  
Rui-Ping Pang ◽  
Kai-Feng Shen ◽  
Manfred Zimmermann ◽  
Wen-Jun Xin ◽  
...  
Keyword(s):  
Dorsal Root Ganglion ◽  
Nerve Injury ◽  
Sodium Channels ◽  
Dorsal Root ◽  
Motor Nerve ◽  
Dorsal Root Ganglion Neurons ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Tnf Α ◽  
Ganglion Neurons

Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons

2013 ◽  
Vol 247 ◽  
pp. 466-475 ◽  
Author(s):  
Kai-Feng Shen ◽  
He-Quan Zhu ◽  
Xu-Hong Wei ◽  
Jun Wang ◽  
Yong-Yong Li ◽  
...  
Keyword(s):  
Dorsal Root Ganglion ◽  
Sodium Channels ◽  
Dorsal Root ◽  
Interleukin 10 ◽  
Dorsal Root Ganglion Neurons ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Ganglion Neurons

Inhibition of voltage-gated sodium channels by bisphenol A in mouse dorsal root ganglion neurons

2011 ◽  
Vol 1378 ◽  
pp. 1-8 ◽  
Author(s):  
Qiang Wang ◽  
Jie Cao ◽  
Qin Zhu ◽  
Chunye Luan ◽  
Xiaodong Chen ◽  
...  
Keyword(s):  
Dorsal Root Ganglion ◽  
Bisphenol A ◽  
Sodium Channels ◽  
Dorsal Root ◽  
Dorsal Root Ganglion Neurons ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Mouse Dorsal Root Ganglion ◽  
Ganglion Neurons
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