scholarly journals Tetrodotoxin: A New Strategy to Treat Visceral Pain?

Toxins ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 496
Author(s):  
Ana Campos-Ríos ◽  
Lola Rueda-Ruzafa ◽  
Salvador Herrera-Pérez ◽  
Paula Rivas-Ramírez ◽  
José Antonio Lamas
Keyword(s):  
Action Potentials ◽  
Channel Blocker ◽  
Visceral Pain ◽  
Visceral Hypersensitivity ◽  
Afferent Neurons ◽  
Sodium Channel Blocker ◽  
Voltage Gated Sodium Channels ◽  
New Strategy ◽  
Specific Receptors

Visceral pain is one of the most common symptoms associated with functional gastrointestinal (GI) disorders. Although the origin of these symptoms has not been clearly defined, the implication of both the central and peripheral nervous systems in visceral hypersensitivity is well established. The role of several pathways in visceral nociception has been explored, as well as the influence of specific receptors on afferent neurons, such as voltage-gated sodium channels (VGSCs). VGSCs initiate action potentials and dysfunction of these channels has recently been associated with painful GI conditions. Current treatments for visceral pain generally involve opioid based drugs, ≠≠which are associated with important side-effects and a loss of effectiveness or tolerance. Hence, efforts have been intensified to find new, more effective and longer-lasting therapies. The implication of VGSCs in visceral hypersensitivity has drawn attention to tetrodotoxin (TTX), a relatively selective sodium channel blocker, as a possible and promising molecule to treat visceral pain and related diseases. As such, here we will review the latest information regarding this toxin that is relevant to the treatment of visceral pain and the possible advantages that it may offer relative to other treatments, alone or in combination.

A Time-Dependent Excitability change in the soma of an identified Insect Motoneurone

1992 ◽  
Vol 162 (1) ◽  
pp. 251-263
Author(s):  
JULES C. HANCOX ◽  
ROBERT M. PITMAN
Keyword(s):  
Cell Body ◽  
Action Potentials ◽  
Periplaneta Americana ◽  
Channel Blocker ◽  
Time Dependent ◽  
Sodium Channel Blocker ◽  
Plateau Potentials ◽  
Excitability Change ◽  
Membrane Oscillations

Long-term, current-clamp recordings were made from the cell body of the fast coxal depressor motoneurone (Df) of the third thoracic ganglion of the cockroach Periplaneta americana. In freshly dissected preparations the response to shortduration, suprathreshold, depolarising current pulses was a graded series of damped membrane oscillations similar to those reported previously in this neurone. The response to current injection changed, however, with increasing time after setting up the preparation: cells developed the ability to exhibit all-ornone action potentials. Their amplitude, however, was usually insufficient to overshoot 0 m V. Our observations suggest that the enhancement in excitability is dependent on time following dissection rather than on time following impalement. Recordings taken from neurone somata mechanically divided from their processes indicated that the time-dependent changes in excitability were not attributable to changes in synaptic input to the neurone and, moreover, that the cell body was involved in action potential genesis. The action potentials were resistant to treatment with the sodium channel blocker tetrodotoxin (up to 10−5 mol l−1), but were reversibly abolished when preparations were bathed in saline containing cadmium ions (1 mmol l−1) or manganese ions (20 or 40 mmol l−1) and, therefore, the inward current underlying these events was largely, if not entirely, carried by calcium ions. These time-dependent action potentials can co-exist with plateau potentials. In neurones giving both plateau potentials and time-dependent action potentials, plateau potentials can drive action potentials in bursts.

scholarly journals Microglia: a newly discovered role in visceral hypersensitivity?

2006 ◽  
Vol 2 (4) ◽  
pp. 271-277 ◽  
Author(s):  
Carl Y. Saab ◽  
Jing Wang ◽  
Chunping Gu ◽  
Kirsten N. Garner ◽  
Elie D. Al-Chaer
Keyword(s):  
Visceral Pain ◽  
Thermal Hyperalgesia ◽  
Radiant Heat ◽  
Pain Modulation ◽  
Visceral Hypersensitivity ◽  
Visceral Sensitivity ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Before And After

AbstractGiven the growing body of evidence for a role of glia in pain modulation, it is plausible that the exaggerated visceral pain in chronic conditions might be regulated by glial activation. In this study, we have investigated a possible role for microglia in rats with chronic visceral hypersensitivity and previously documented altered neuronal function. Experiments were performed on adult male Sprague-Dawley rats pre-treated with neonatal colon irritation (CI) and on control rats. Effects of fractalkine (FKN, a chemokine involved in neuron-to-microglia signaling) and of minocycline (an inhibitor of microglia) on visceral sensitivity were examined. Visceral sensitivity was assessed by recording the electromyographic (EMG) responses to graded colorectal distension (CRD) in mildly sedated rats. Responses to CRD were recorded before and after injection of FKN, minocycline or vehicle. Somatic thermal hyperalgesia was measured by latency of paw withdrawal to radiant heat. The pattern and intensity of microglial distribution at L6–S2 in the spinal cord was also compared in rats with CI and controls by fluorescence microscopy using OX-42. Results show that: (1) FKN significantly facilitated EMG responses to noxious CRD by >52% in control rats. FKN also induced thermal hyperalgesia in control rats, consistent with previous reports; (2) minocycline significantly inhibited EMG responses to noxious CRD by >70% in rats with CI compared to controls 60 min after injection. The anti-nociceptive effect of minocycline lasted for 180 min in rats with CI, reaching peak values 60 min after injection. Our results show that FKN enhances visceral and somatic nociception, whereas minocycline inhibits visceral hypersensitivity in chronically sensitized rats, which indicates a role for microglia in visceral hypersensitivity.

Computer Simulation of the Neuronal Action Potential

1988 ◽  
Vol 15 (1) ◽  
pp. 46-47 ◽  
Author(s):  
Paul R. Solomon ◽  
Scott Cooper ◽  
Dean Pomerleau
Keyword(s):  
Computer Simulation ◽  
Action Potential ◽  
Sodium Channel ◽  
Computer Simulations ◽  
Action Potentials ◽  
Channel Blocker ◽  
Neuronal Membrane ◽  
Excitatory Postsynaptic Potential ◽  
Sodium Channel Blocker ◽  
Postsynaptic Potential

A series of computer simulations of the neuronal resting and action potentials are described. These programs are designed to allow the user to observe the movement of ions across a neuronal membrane during: (a) an action potential, (b) a subthreshold excitatory postsynaptic potential (EPSP), (c) an inhibitory postsynaptic potential, and (d) a suprathreshold EPSP in the presence of the sodium channel blocker tetrodotoxin (TTX).

Regulation of Auditory Responses in the Central Nucleus of the Inferior Colliculus by Tetraethylammonium-Sensitive Potassium Channels

2004 ◽  
Vol 91 (5) ◽  
pp. 2194-2204 ◽  
Author(s):  
Huiming Zhang ◽  
Shu Hui Wu ◽  
Jack B. Kelly
Keyword(s):  
Potassium Channels ◽  
Inferior Colliculus ◽  
Action Potentials ◽  
Channel Blocker ◽  
Central Nucleus ◽  
Evoked Responses ◽  
Spontaneous Firing ◽  
Temporal Properties ◽  
Auditory Responses

The role of potassium channels in regulating spontaneous firing and sound-evoked responses in the central nucleus of the inferior colliculus was studied by recording single-unit activity before and during iontophoretic application of a nonspecific potassium channel blocker, tetraethylammonium (TEA). Tone bursts and sinusoidal amplitude-modulated tones were used to evoke auditory responses. Our results show that release of TEA increased the width of spikes for all neurons tested. There was an increase in spontaneous firing for most of the neurons. There was also an increase in responses to tone bursts for most of the neurons, although in some cases there was a reduction in the evoked responses. TEA also increased the firing rate in responses to sinusoidal amplitude-modulated sounds in the majority of the neurons tested. For some neurons, the change in firing reduced the selectivity of responses for particular rates of modulation. There was also a reduction in the synchrony of action potentials to the modulation envelope in many cells. Our results show that potassium channels are important for regulating the strength of sound-evoked responses and the level of spontaneous activity, and determining the temporal properties of responses to amplitude-modulated sounds.

Role of L-Type Ca2+ Channels in Transmitter Release From Mammalian Inner Hair Cells. II. Single-Neuron Activity

2002 ◽  
Vol 87 (6) ◽  
pp. 2734-2740 ◽  
Author(s):  
Donald Robertson ◽  
Bardia Paki
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Transmitter Release ◽  
Channel Blocker ◽  
Neuron Activity ◽  
Afferent Neurons ◽  
Inner Hair Cell ◽  
Inner Hair Cells ◽  
Firing Rates

Previously reported changes in the gross sound-evoked cochlear potentials after intracochlear perfusion of nimodipine suggest that dihydropyridine-sensitive Ca2+ channels (L-type) control the sound-evoked release of transmitter from the inner hair cells of the mammalian cochlea. In the present study, we combined recording of the action potentials of single primary auditory afferent neurons with intracochlear perfusion to further investigate the role of voltage-gated Ca2+ channels at this synapse. Spontaneous action potential firing rates were depressed by the L-type channel blocker nimodipine, but were elevated by S(−) BAY K8644, an L-type channel agonist. Sound-evoked responses of single primary afferents were depressed by nimodipine in a manner that was consistent with a block at the inner hair cell-afferent dendrite synapse. Perfusions with solutions containing the N-type channel blocker conotoxin GVIA did not differ in their effects from control artificial perilymph perfusions. The results extend the conclusions of the earlier study by showing that L-type Ca2+channels are primarily responsible for controlling both spontaneous and sound-evoked transmitter release from inner hair cells. In addition it was found that afferent neurons with widely different spontaneous firing rates were all sensitive to nimodipine and to BAY K8644, suggesting that the multiple synaptic outputs of each inner hair cell are under the control of only one major type of Ca2+ channel.

Amiloride-sensitive signals and NaCl preference and appetite: a lick-rate analysis

2000 ◽  
Vol 279 (4) ◽  
pp. R1403-R1411 ◽  
Author(s):  
Michelle D. Brot ◽  
Chae H. Watson ◽  
Ilene L. Bernstein
Keyword(s):  
Channel Blocker ◽  
Lick Rate ◽  
Chorda Tympani ◽  
Sodium Channel Blocker ◽  
Afferent Pathway ◽  
Afferent Pathways ◽  
Rate Analysis ◽  
Long Access ◽  
Modest Effect

Rats prefer hypotonic and isotonic NaCl solutions to water in long-access drinking paradigms. To focus on the role of taste signals in NaCl preference, licking patterns of rats with 30-s exposure to NaCl solutions (0–0.5 M) were examined when they were either water deprived, sodium depleted, or not deprived (NaCl mixed in dilute sucrose). In all three conditions, rats displayed a preference for NaCl. The addition of 100 μM amiloride, a sodium channel blocker, to NaCl did not change rats' licking when they were sodium replete but dramatically reduced licking when they were deplete. Transection of the chorda tympani (CT) nerve, an afferent pathway for amiloride-sensitive Na+ signals, had no effect on NaCl preference in nondeprived rats and only a modest effect on those that were Na+ deplete. Amiloride was found to exert significant suppression of NaCl intake in Na+-depleted rats with transection of the CT, supporting the existence of other afferent pathways for transmission of amiloride-sensitive Na+signalling. Together, these studies argue for the involvement of different neural signalling mechanisms in NaCl preference in the presence and absence of explicit Na+ need.

scholarly journals Bicarbonate therapy for unstable propafenone-induced wide complex tachycardia

CJEM ◽  
2004 ◽  
Vol 6 (05) ◽  
pp. 349-356 ◽  
Author(s):  
Jeff Brubacher
Keyword(s):  
Blood Pressure ◽  
Sinus Rhythm ◽  
Channel Blocker ◽  
Cardiac Toxicity ◽  
Clinical Status ◽  
Sodium Channel Blocker ◽  
Wide Complex Tachycardia ◽  
Bicarbonate Therapy ◽  
Qrs Duration

ABSTRACTA previously healthy 73-year-old woman presented to hospital with acute atrial fibrillation. After intravenous procainamide failed to restore sinus rhythm, she was treated with 300 mg of oral propafenone and discharged with a prescription for propafenone and propranolol. Six hours later she took 150 mg of propafenone as prescribed. Within 1 hour she became dyspneic and collapsed. On arrival in hospital she was unconscious, with a wide complex tachycardia and no obtainable blood pressure. After defibrillation and lidocaine, she converted to a wide complex sinus rhythm, but remained profoundly hypotensive despite intravenous epinephrine and dopamine. Hypertonic sodium bicarbonate (HCO3) was administered and, shortly thereafter, her blood pressure increased, her QRS duration normalized and her clinical status improved dramatically. In this case of severe refractory propafenone-related cardiac toxicity, intravenous HCO3led to a profound clinical improvement. Emergency physicians should be familiar with the syndrome of sodium-channel blocker poisoning and recognize the potentially important role of bicarbonate in its treatment.

scholarly journals Glutamate Transporter GLT-1 Upregulation Attenuates Visceral Nociception and Hyperalgesia via Spinal Mechanisms Not Related to Anti-Inflammatory or Probiotic Effects

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Y. Lin ◽  
K. Roman ◽  
K. D. Foust ◽  
B. K. Kaspar ◽  
M. T. Bailey ◽  
...  
Keyword(s):  
Visceral Pain ◽  
Glutamate Transporter ◽  
Visceral Hypersensitivity ◽  
Nociceptive Response ◽  
Excitatory Neurotransmitter ◽  
Physician Visits ◽  
Over Expression ◽  
Visceral Nociception ◽  
Virus Serotype

Visceral pain is the most common reason for physician visits in US. Glutamate is the major excitatory neurotransmitter and mediates visceral nociceptive neuro-transmission and hypersensitivity. Removal of extracellular glutamate is predominantly mediated by glial glutamate transporter-1 (GLT-1). The pharmacological approach to up-regulate GLT-1 by 1 week administration of ceftriaxone (CTX) has been successful to mitigate visceral nociception. The present study shows that intrathecal delivery of selective GLT-1 antagonist dihydrokainate reversed CTX-blunted visceral nociceptive response, suggesting a spinal site of action. The role of GLT-1 up-regulation in animal models of colitis was studied. CTX treatment reversed TNBS-induced visceral hypersensitivity. In addition, CTX treatment initiated one week after the onset of DSS-induced visceral inflammation also attenuated visceral hypersensitivity, revealing a potential therapeutic effect. Cephalothin, a cephalosporin antibiotic lacking GLT-1 induction activity, failed to attenuate visceral nociception. CTX-induced changes in fecal microbiota do not support a role of probiotic effects in mitigating visceral nociception/hypersensitivity. Finally, adeno-associated virus serotype 9-mediated GLT-1 over-expression was effective to mitigate visceromotor response to 60 mmHg colo-rectal distension. These studies indicate that GLT-1 over-expression is a novel and effective method to attenuate visceral nociception, and is deserving of further study as a translationally relevant approach to treat visceral pain.

scholarly journals The Role of the Persistent Sodium Current in Epilepsy

2020 ◽  
pp. 153575972097397
Author(s):  
Eric R. Wengert ◽  
Manoj K. Patel
Keyword(s):  
Action Potentials ◽  
Cell Function ◽  
Sodium Current ◽  
Persistent Sodium Current ◽  
Sodium Ions ◽  
Pathogenic Role ◽  
The Past ◽  
Voltage Gated Sodium Channels ◽  
Total Sodium

Voltage-gated sodium channels (VGSCs) are foundational to excitable cell function: Their coordinated passage of sodium ions into the cell is critical for the generation and propagation of action potentials throughout the nervous system. The classical paradigm of action potential physiology states that sodium passes through the membrane only transiently (1-2 milliseconds), before the channels inactivate and cease to conduct sodium ions. However, in reality, a small fraction of the total sodium current (1%-2%) remains at steady state despite prolonged depolarization. While this persistent sodium current (INaP) contributes to normal physiological functioning of neurons, accumulating evidence indicates a particularly pathogenic role for an elevated INaP in epilepsy (reviewed previously 1 ). Due to significant advances over the past decade of epilepsy research concerning the importance of INaP in sodium channelopathies, this review seeks to summarize recent evidence and highlight promising novel anti-seizure medication strategies through preferentially targeting INaP.

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