Paper 2 Answers
James Day, Amy Thomson, Tamsin McAllister, Nawal Bahal in Get Through, 2014
Generation of an action potential: Above threshold potential, voltage-gated sodium channels open allowing rapid sodium influx into the cell. Membrane potential rises to +30 mV.Voltage-gated sodium channels close and potassium channels open. Potassium ions move out of the cell down their concentration gradient. Membrane potential drops again; this is repolarization.Membrane potential overshoots below resting membrane potential; this is hyperpolarization.Na+/K+−ATPase pump pumps sodium ions back out of the cell and potassium ions back into the cell to restore resting membrane potential.
Low-Dose Naltrexone
Sahar Swidan, Matthew Bennett in Advanced Therapeutics in Pain Medicine, 2020
Adaptive pain is a result of tissue damage either from trauma or surgery and is propagated through the processes of transduction, conduction, transmission, perception, and modulation. Transduction involves the release of cytokines and chemokines from nociceptors in the somatic and visceral structures activated by mechanical, thermal, or chemical stimuli. Conduction involves the generation of action potentials by the depolarization of voltage-gated sodium channels. Transmission through afferent nerve fibers causes the release of glutamate and substance P acting as excitatory neurotransmitters, ultimately propagating the pain signal to the thalamus, where the signal is relayed to higher cortical structures. Perception is the result of the pain signals that reach the higher cortical structures becoming a conscious experience. Modulation is the result of many different neurotransmitters and receptor interactions that either strengthen or attenuate the pain signal. Excitatory neurotransmitters involved in pain include glutamate and substance P. Inhibitory neurotransmitters involved in pain include enkephalins, β-endorphins, GABA, norepinephrine, and serotonin. Additionally, NMDA receptors seem to influence opioid receptor responsiveness to exogenous and endogenous opioids.
Pharmacology of Local Anesthetics
Pamela E. Macintyre, Stephan A. Schug in Acute Pain Management, 2021
Local anesthetics block voltage-gated sodium channels in cell membranes (Becker & Reed, 2012). They prevent the influx of sodium ions into cells and thereby the generation of action potentials and the conduction of nerve impulses (see Figure 5.1). Local anesthetics may also modify a number of other neuronal membrane channels or even receptors, contributing to their effect (Lirk et al, 2018). Interaction with calcium, potassium, and hyperpolarization-gated ion channels and ligand-gated channels (for example NMDA receptors) have been identified. Therefore, local anesthetics interfere with neuronal function in multiple other ways, primarily by cell membrane effects. Last, but not least, effects on G-protein coupled receptors may explain some of the antiinflammatory effects of local anesthetics.
Pharmacotherapeutic Options for Chronic Refractory Cough
Published in Expert Opinion on Pharmacotherapy, 2020
Voltage-gated sodium channel (NaV) has an essential role in action potential generation and propagation [80]. Thus, NaV is considered as an attractive therapeutic target in CRC. Inhaled lidocaine, which has little selectivity on different NaV subtypes, gained clinical attention [81]; however, its antitussive effect has not been confirmed in a placebo-controlled study of CRC patients. There was 1 RCT identified in the clinical trial registry (NCT01252225); however, the results were not posted. Recently, more scientific attention was given to novel NaV blockers. However, two inhaled drugs, GSK2339345 and carcainium chloride, were not effective in recent early phase trials [82,83]. Thus, the clinical relevance of NaV blockade in CRC warrants further investigation.
Neuropathic pain: preclinical and early clinical progress with voltage-gated sodium channel blockers
Published in Expert Opinion on Investigational Drugs, 2020
Mikhail Kushnarev, Iulia Paula Pirvulescu, Kenneth D. Candido, Nebojsa Nick Knezevic
Voltage-gated sodium channels (Navs or VGSCs) are a family of transmembrane proteins that plays an important role in electrical signaling of cells in various tissues. Nine isoforms of Nav channels have been identified to date, nomenclated Nav1.1 to Nav1.9 [10]. Traditionally, Nav subtypes have been classified according to their response to tetrodotoxin (TTX) – a powerful neurotoxin isolated from pufferfish, which is a highly potent inhibitor of voltage-gated sodium channels. TTX-sensitive Nav channels, inhibited at low nanomolar concentrations of TTX, include Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6, and Nav1.7. TTX-resistant isoforms: Nav1.5, Nav1.8, and Nav1.9, are blocked at high micromolar concentration of TTX [10,11]. These Nav subtypes are expressed in various tissues and play an important role in a multitude of physiological functions (Table 1) [10–12,16,17].
miR-384-5p ameliorates neuropathic pain by targeting SCN3A in a rat model of chronic constriction injury
Published in Neurological Research, 2020
Guangyao Ye, Yu Zhang, Jingsong Zhao, Yuebo Chen, Lingsi Kong, Chaoxu Sheng, Liyong Yuan
Voltage-gated sodium channels (VGSC) are important in nervous system development. Dysregulation of their encoding gene expression has been linked to neurological diseases. Strong evidence indicated that several VGSCs play important roles in the initiation and generation of action potentials in neurons of central and peripheral nervous systems [30]. Among these VGSCs, Nav1.3 (encoded by SCN3A), an isoform of the tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channel (VGSC), has been demonstrated to be involved in the development of chronic pain. For instance, Nav1.3 is upregulated in spinal microglia following spinal nerve ligation [32]. Waxman et al. reported that downregulation of SCN3A reversed thermal hyperalgesia and mechanical allodynia in CCI rats [33]. This study examined the time-course expression of SCN3A in CCI rats. SCN3A was upregulated since day 3 after CCI, and this upregulation peaked on day 7 after induction and kept stable till day 21. In addition, SCN3A was indicated as a direct target of miR-384-5p, and miR-384-5p negatively regulated SCN3A expression both in vitro and in vivo. Furthermore, overexpression of SCN3A could reverse the suppressive effect of miR-384-5p in the progression of neuropathic pain. In the future, more studies will be needed to study the crosstalk involving SCN3A in the progression of neuropathic pain.
Related Knowledge Centers
- Glia
- Integral Membrane Protein
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- Cell Membrane
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- Cation Channel Superfamily
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