Colonic inflammation increases Na+ currents in bladder sensory neurons

Neuroreport ◽  
2004 ◽  
Vol 15 (17) ◽  
pp. 2601-2605 ◽  
Author(s):  
Anna P. Malykhina ◽  
Chao Qin ◽  
Robert D. Foreman ◽  
Hamid I. Akbarali
Keyword(s):  
Sensory Neurons ◽  
Colonic Inflammation ◽  
Na Currents

scholarly journals Voltage-gated Na+ currents in human dorsal root ganglion neurons

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Xiulin Zhang ◽  
Birgit T Priest ◽  
Inna Belfer ◽  
Michael S Gold
Keyword(s):  
Sensory Neurons ◽  
Tissue Injury ◽  
Dorsal Root Ganglion Neurons ◽  
Pharmacological Properties ◽  
Pain Mechanisms ◽  
Voltage Gated ◽  
Whole Cell Patch Clamp ◽  
Na Currents ◽  
Ganglion Neurons ◽  
Peripheral Sensory

Available evidence indicates voltage-gated Na+ channels (VGSCs) in peripheral sensory neurons are essential for the pain and hypersensitivity associated with tissue injury. However, our understanding of the biophysical and pharmacological properties of the channels in sensory neurons is largely based on the study of heterologous systems or rodent tissue, despite evidence that both expression systems and species differences influence these properties. Therefore, we sought to determine the extent to which the biophysical and pharmacological properties of VGSCs were comparable in rat and human sensory neurons. Whole cell patch clamp techniques were used to study Na+ currents in acutely dissociated neurons from human and rat. Our results indicate that while the two major current types, generally referred to as tetrodotoxin (TTX)-sensitive and TTX-resistant were qualitatively similar in neurons from rats and humans, there were several differences that have important implications for drug development as well as our understanding of pain mechanisms.

The Effects of Class Ic Antiarrhythmics on Tetrodotoxin-Resistant Na+ Currents in Rat Sensory Neurons

2004 ◽  
pp. 464-471 ◽  
Author(s):  
Yoko Osawa ◽  
Akiyoshi Oda ◽  
Hiroki Iida ◽  
Shigeaki Tanahashi ◽  
Shuji Dohi
Keyword(s):  
Sensory Neurons ◽  
Na Currents

scholarly journals 3’-O-Methylorobol Inhibits the Voltage-Gated Sodium Channel Nav1.7 with Anti-Itch Efficacy in A Histamine-Dependent Itch Mouse Model

2019 ◽  
Vol 20 (23) ◽  
pp. 6058 ◽  
Author(s):  
Fan Zhang ◽  
Ying Wu ◽  
Shuwen Xue ◽  
Shuangyan Wang ◽  
Chunlei Zhang ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Sensory Neurons ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Cell Voltage ◽  
Comparable Efficacy ◽  
Drg Neurons ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Na Currents

An itch is a clinical complication that affects millions of patients. However, few treatment options are available. The voltage-gated sodium channel Nav1.7 is predominantly expressed in peripheral sensory neurons and is responsible for the rising phase of action potentials, thereby mediating nociceptive conduction. A gain-of-function mutation of Nav1.7 results in the hyperexcitability of sensory neurons and causes the inherited paroxysmal itch. Conversely, a monoclonal antibody that selectively inhibits Nav1.7 is able to effectively suppress the histamine-dependent itch in mice. Therefore, Nav1.7 inhibitors may possess the potential to relieve the itch. In the present study, using whole-cell voltage-clamp recordings, we demonstrated that 3’-O-methylorobol inhibited Na+ currents in Nav1.7-CHO cells and tetrodotoxin-sensitive Na+ currents in mouse dorsal root ganglion (DRG) neurons with IC50 (half-maximal inhibitory concentration) values of 3.46 and 6.60 μM, respectively. 3’-O-methylorobol also suppressed the tetrodotoxin-resistant Na+ currents in DRG neurons, though with reduced potency (~43% inhibition at 30 µM). 3’-O-methylorobol (10 µM) affected the Nav1.7 by shifting the half-maximal voltage (V1/2) of activation to a depolarizing direction by ~6.76 mV, and it shifted the V1/2 of inactivation to a hyperpolarizing direction by ~16.79 mV. An analysis of 3’-O-methylorobol activity toward an array of itch targets revealed that 3’-O-methylorobol was without effect on histamine H1 receptor, TRPV1, TRPV3, TRPV4, TRPC4 and TRPM8. The intrathecal administration of 3’-O-methylorobol significantly attenuated compound 48/80-induced histamine-dependent spontaneous scratching bouts and the expression level of c-fos in the nuclei of spinal dorsal horn neurons with a comparable efficacy to that of cyproheptadine. Our data illustrated the therapeutic potential for 3’-O-methylorobol for histamine-dependent itching, and the small molecule inhibition of Nav1.7 may represent a useful strategy to develop novel therapeutics for itching.

scholarly journals Inhibition of Voltage-Gated Na+ Currents in Sensory Neurons by the Sea Anemone Toxin APETx2

2012 ◽  
Vol 102 (3) ◽  
pp. 324a-325a
Author(s):  
Maxime G. Blanchard ◽  
Lachlan D. Rash ◽  
Stephan Kellenberger
Keyword(s):  
Sensory Neurons ◽  
Sea Anemone ◽  
Voltage Gated ◽  
Na Currents ◽  
Sea Anemone Toxin

Two TTX-resistant Na+ currents in mouse colonic dorsal root ganglia neurons and their role in colitis-induced hyperexcitability

2004 ◽  
Vol 287 (4) ◽  
pp. G845-G855 ◽  
Author(s):  
Michael J. Beyak ◽  
Noor Ramji ◽  
Karmen M. Krol ◽  
Michael D. Kawaja ◽  
Stephen J. Vanner
Keyword(s):  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Neuronal Excitability ◽  
Distal Colon ◽  
Inactivation Kinetics ◽  
Drg Neurons ◽  
Trinitrobenzenesulfonic Acid ◽  
Na Currents ◽  
Dorsal Root Ganglia Neurons

The composition of Na+ currents in dorsal root ganglia (DRG) neurons depends on their neuronal phenotype and innervation target. Two TTX-resistant (TTX-R) Na+ currents [voltage-gated Na channels (Na v)] have been described in small DRG neurons; one with slow inactivation kinetics (Na v1.8) and the other with persistent kinetics (Na v1.9), and their modulation has been implicated in inflammatory pain. This has not been studied in neurons projecting to the colon. This study examined the relative importance of these currents in inflammation-induced changes in a mouse model of inflammatory bowel disease. Colonic sensory neurons were retrogradely labeled, and colitis was induced by instillation of trinitrobenzenesulfonic acid (TNBS) into the lumen of the distal colon. Seven to ten days later, immunohistochemical properties were characterized in controls, and whole cell recordings were obtained from small (<40 pF) labeled DRG neurons from control and TNBS animals. Most neurons exhibited both fast TTX-sensitive (TTX-S)- and slow TTX-R-inactivating Na+ currents, but persistent TTX-R currents were uncommon (<15%). Most labeled neurons were CGRP (79%), tyrosine kinase A (trkA) (84%) immunoreactive, but only a small minority bind IB4 (14%). TNBS-colitis caused ulceration, thickening of the colon and significantly increased neuronal excitability. The slow TTX-R-inactivating Na current density (Na v1.8) was significantly increased, but other Na currents were unaffected. Most small mouse colonic sensory neurons are CGRP, trkA immunoreactive, but not isolectin B4 reactive and exhibit fast TTX-S, slow TTX-R, but not persistent TTX-R Na+ currents. Colitis-induced hyperexcitability is associated with increased slow TTX-R (Na v1.8) Na+ current. Together, these findings suggest that colitis alters trkA-positive neurons to preferentially increase slow TTX-R Na+ (Na v1.8) currents.

The Local Anesthetic n-Butyl-p-Aminobenzoate Selectively Affects Inactivation of Fast Sodium Currents in Cultured Rat Sensory Neurons

1995 ◽  
Vol 82 (6) ◽  
pp. 1463-1473. ◽  
Author(s):  
R. J. Van den Berg ◽  
P. F. Van Soest ◽  
Z. Wang ◽  
R. J. E. Grouls ◽  
H. H. M. Korsten
Keyword(s):  
Action Potential ◽  
Sensory Neurons ◽  
Local Anesthetic ◽  
Action Potentials ◽  
Sodium Current ◽  
Short Exposure ◽  
Na Channels ◽  
Firing Threshold ◽  
Na Currents ◽  
Ganglion Neurons

Background Aqueous suspensions of the local anesthetic n-butyl-p-aminobenzoate (BAB), epidurally applied in terminal cancer patients, resulted in a sensory blockade, lasting up to several months. To investigate the mechanism of action on the cellular level, the effect of 100 microM BAB on Na+ action potentials and on Na+ currents in dorsal root ganglion neurons from neonatal rats was studied. Methods Small neurons grown in cell culture were selected for patch-clamp measurements. Both Na+ action potentials, evoked by current pulses of increasing amplitude (current clamp) and Na+ currents, activated at different membrane potentials (voltage clamp), were investigated in the absence and presence of 100 microM BAB. The local anesthetic was applied by external perfusion for 2 or 10 min. Results In the presence of 100 microM BAB, either the firing threshold was raised or the action potential was abolished. The maximal peak conductances, underlying the fast sodium current INa,F and the slow sodium current INa,5, were not changed. However, the inactivation of INa,F was increased by BAB. The sigmoid inactivation curve shifted 12 mV toward hyperpolarizing membrane voltages, whereas no changes were found for the inactivation of the slow Na+ current. Only at short exposure times of 2 min, the effects of BAB could be reversed during a 10-min wash-out. Conclusions BAB dramatically increased the firing threshold, and in part of the sensory neurons, it blocked the action potential. The inactivation of the fast Na+ channels, but not of the slow Na+ channels, was increased by BAB. Thus, the block of fast Na+ channels by BAB may contribute to epidural analgesia. At exposure times of 10 min, the effect of BAB was not reversible. This probably originates from its high lipid-solubility, which may be an important factor in determining the duration of the block in vivo.

Effects of Class 1C Antiarrhythmics on Tetrodotoxin-Resistant Na+ Currents in Rat Sensory Neurons

2002 ◽  
Vol 96 (Sup 2) ◽  
pp. A833
Author(s):  
Yoko Osawa ◽  
Akiyoshi Oda ◽  
Shigeaki Tanahashi ◽  
Hiroki Iida ◽  
Shuji Dohi
Keyword(s):  
Sensory Neurons ◽  
Na Currents

Inactivation of Macroscopic Late Na+ Current and Characteristics of Unitary Late Na+ Currents in Sensory Neurons

1998 ◽  
Vol 80 (5) ◽  
pp. 2538-2549 ◽  
Author(s):  
Mark D. Baker ◽  
Hugh Bostock
Keyword(s):  
Sensory Neurons ◽  
Dorsal Root Ganglion Neurons ◽  
Potential Range ◽  
Whole Cell ◽  
Whole Cells ◽  
Adult Rat ◽  
Na Currents ◽  
Steady State Inactivation ◽  
Cell Current ◽  
Ganglion Neurons

Baker, Mark D. and Hugh Bostock. Inactivation of macroscopic late Na+ current and characteristics of unitary late Na+ currents in sensory neurons. J. Neurophysiol. 80: 2538–2549, 1998. Na+ currents in adult rat large dorsal root ganglion neurons were recorded during long duration voltage-clamp steps by patch clamping whole cells and outside-out membrane patches. Na+ current present >60 ms after the onset of a depolarizing pulse (late Na+ current) underwent partial inactivation; it behaved as the sum of three kinetically distinct components, each of which was blocked by nanomolar concentrations of tetrodotoxin. Inactivation of one component (late-1) of the whole cell current reached equilibrium during the first 60 ms; repolarizing to −40 or −50 mV from potentials of −30 mV or more positive gave rise to a characteristic increase in current (τ ≥ 5 ms), attributed to removal of inactivation. A second component (late-2) underwent slower inactivation (τ > 80 ms) at potentials more positive than −80 mV, and steady-state inactivation appeared complete at −30 mV. In small membrane patches, bursts of brief openings (γ = 13–18 pS) were usually recorded. The distribution of burst durations indicated that two populations of channel were present with inactivation rates corresponding to late-1 and late-2 macroscopic currents. The persistent Na+ current in the whole cell that extended to potentials more positive than −30 mV appeared to correspond to sporadic, brief openings that were recorded in patches (mean open time ∼0.1 ms) over a wide potential range. None of the three types of gating described corresponded to activation/inactivation gating overlap of fast transient currents.

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