The opioid oxycodone use‐dependently inhibits the cardiac sodium channel Na<sub>V</sub>1.5

Meents, Jannis; Juhász, Krisztina; Stölzle‐Feix, Sonja; Peuckmann‐Post, Vera; Rolke, Roman; Lampert, Angelika

doi:10.1111/bph.14348

Cited by 14 publications

(6 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Due to the difficulty in developing isoform-specific Na v channel blockers, newly developed, relatively non-specific, voltage-gated sodium channel blockers often cause adverse effects in patients ( Mulroy, 2002 ; de Lera Ruiz and Kraus, 2015 ; Dokken and Fairley, 2021 ). Because some opioid analogs such as fentanyl, oxycodone, buprenorphine, meperidine, and loperamide block sodium channels ( Wagner et al ., 1999 ; Olschewski et al ., 2001 ; Wolff et al ., 2004 ; Haeseler et al ., 2006 ; Leffler et al ., 2012 ; Wu et al ., 2017 ; Meents et al ., 2018 ), we aimed to determine whether tramadol also blocks sodium channels.…”

Section: Discussionmentioning

confidence: 99%

Tramadol as a Voltage-Gated Sodium Channel Blocker of Peripheral Sodium Channels Na_v1.7 and Na_v1.5

Bok

Kim

Cho

et al. 2023

Biomol Ther (Seoul)

View full text Add to dashboard Cite

Tramadol is an opioid analog used to treat chronic and acute pain. Intradermal injections of tramadol at hundreds of millimoles have been shown to produce a local anesthetic effect. We used the whole-cell patch-clamp technique in this study to investigate whether tramadol blocks the sodium current in HEK293 cells, which stably express the pain threshold sodium channel Nav1.7 or the cardiac sodium channel Nav1.5. The half-maximal inhibitory concentration of tramadol was 0.73 mM for Nav1.7 and 0.43 mM for Nav1.5 at a holding potential of -100 mV. The blocking effects of tramadol were completely reversible. Tramadol shifted the steady-state inactivation curves of Nav1.7 and Nav1.5 toward hyperpolarization. Tramadol also slowed the recovery rate from the inactivation of Nav1.7 and Nav1.5 and induced stronger use-dependent inhibition. Because the mean plasma concentration of tramadol upon oral administration is lower than its mean blocking concentration of sodium channels in this study, it is unlikely that tramadol in plasma will have an analgesic effect by blocking Nav1.7 or show cardiotoxicity by blocking Nav1.5. However, tramadol could act as a local anesthetic when used at a concentration of several hundred millimoles by intradermal injection and as an antiarrhythmic when injected intravenously at a similar dose, as does lidocaine.

show abstract

Section: Discussionmentioning

confidence: 99%

Tramadol as a Voltage-Gated Sodium Channel Blocker of Peripheral Sodium Channels Na_v1.7 and Na_v1.5

Bok

Kim

Cho

et al. 2023

Biomol Ther (Seoul)

View full text Add to dashboard Cite

show abstract

“…If with six groups (f = 0.4, α = 0.05, power = 0.7, N = 12 per group). We referred to the calculated results from this analysis and other studies with similar investigations (Cox et al, 2006;Estacion et al, 2008;Meents et al, 2018). Studies were designed to generate groups of equal size.…”

Section: Data and Statistical Analysismentioning

confidence: 99%

“…For estimation of the number of cells needed per experiment, we performed an a priori analysis for experiments where two groupsassuming normal distribution-were compared (d = 0.8, α = 0.05, power = 0.7, N = 21 per group), for experiments with three groups (f = 0.4, α = 0.05, power = 0.7, N = 18 per group), and for experiments with six groups (f = 0.4, α = 0.05, power = 0.7, N = 12 per group). We referred to the calculated results from this analysis and other studies with similar investigations (Cox et al, 2006;Estacion et al, 2008;Meents et al, 2018). Studies were designed to generate groups of equal size.…”

Section: Data and Statistical Analysismentioning

confidence: 99%

Uncoupling sodium channel dimers restores the phenotype of a pain‐linked Na_v1.7 channel mutation

Rühlmann

Körner

Hausmann

et al. 2020

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

Background and Purpose The voltage‐gated sodium channel Nav1.7 is essential for adequate perception of painful stimuli. Mutations in the encoding gene, SCN9A, cause various pain syndromes in humans. The hNav1.7/A1632E channel mutant causes symptoms of erythromelalgia and paroxysmal extreme pain disorder (PEPD), and its main gating change is a strongly enhanced persistent current. On the basis of recently published 3D structures of voltage‐gated sodium channels, we investigated how the inactivation particle binds to the channel, how this mechanism is altered by the hNav1.7/A1632E mutation, and how dimerization modifies function of the pain‐linked mutation. Experimental Approach We applied atomistic molecular simulations to demonstrate the effect of the mutation on channel fast inactivation. Native PAGE was used to demonstrate channel dimerization, and electrophysiological measurements in HEK cells and Xenopus laevis oocytes were used to analyze the links between functional channel dimerization and impairment of fast inactivation by the hNav1.7/A1632E mutation. Key Results Enhanced persistent current through hNav1.7/A1632E channels was caused by impaired binding of the inactivation particle, which inhibits proper functioning of the recently proposed allosteric fast inactivation mechanism. hNav1.7 channels form dimers and the disease‐associated persistent current through hNav1.7/A1632E channels depends on their functional dimerization status: Expression of the synthetic peptide difopein, a 14‐3‐3 inhibitor known to functionally uncouple dimers, decreased hNav1.7/A1632E channel‐induced persistent currents. Conclusion and Implications Functional uncoupling of mutant hNav1.7/A1632E channel dimers restored their defective allosteric fast inactivation mechanism. Our findings support the concept of sodium channel dimerization and reveal its potential relevance for human pain syndromes.

show abstract

“…The current research focuses on hERG channels, which affect the QT interval most significantly. Recent studies have also identified new mechanisms and ion channel loci, I K1 for example [ 16 , 17 , 47 ].…”

Section: Opioids and Ion Channelmentioning

confidence: 99%

Opioids-Induced Long QT Syndrome: A Challenge to Cardiac Health

Hu,

Song,

Huang

et al. 2024

Cardiovasc Toxicol

View full text Add to dashboard Cite

The challenge posed by opioid overdose has become a significant concern for health systems due to the complexities associated with drug prohibition, widespread clinical use, and potential abuse. In response, healthcare professionals have primarily concentrated on mitigating the hallucinogenic and respiratory depressant consequences of opioid overdose to minimize associated risks. However, it is crucial to acknowledge that most opioids possess the capacity to prolong the QT interval, particularly in cases of overdose, thereby potentially resulting in severe ventricular arrhythmias and even sudden death if timely intervention is not implemented. Consequently, alongside addressing the typical adverse effects of opioids, it is imperative to consider their cardiotoxicity. To enhance comprehension of the correlation between opioids and arrhythmias, identify potential targets for prompt intervention, and mitigate the hazards associated with clinical utilization, an exploration of the interaction between drugs and ion channels, as well as their underlying mechanisms, becomes indispensable. This review primarily concentrates on elucidating the impact of opioid drugs on diverse ion channels, investigating recent advancements in this domain, and attaining a deeper understanding of the mechanisms underlying the prolongation of the QT interval by opioid drugs, along with potential interventions.

show abstract

The opioid oxycodone use‐dependently inhibits the cardiac sodium channel Na_V1.5

Cited by 14 publications

References 30 publications

Tramadol as a Voltage-Gated Sodium Channel Blocker of Peripheral Sodium Channels Na_v1.7 and Na_v1.5

Tramadol as a Voltage-Gated Sodium Channel Blocker of Peripheral Sodium Channels Na_v1.7 and Na_v1.5

Uncoupling sodium channel dimers restores the phenotype of a pain‐linked Na_v1.7 channel mutation

Opioids-Induced Long QT Syndrome: A Challenge to Cardiac Health

Contact Info

Product

Resources

About

The opioid oxycodone use‐dependently inhibits the cardiac sodium channel NaV1.5

Cited by 14 publications

References 30 publications

Tramadol as a Voltage-Gated Sodium Channel Blocker of Peripheral Sodium Channels Nav1.7 and Nav1.5

Tramadol as a Voltage-Gated Sodium Channel Blocker of Peripheral Sodium Channels Nav1.7 and Nav1.5

Uncoupling sodium channel dimers restores the phenotype of a pain‐linked Nav1.7 channel mutation

Opioids-Induced Long QT Syndrome: A Challenge to Cardiac Health

Contact Info

Product

Resources

About

The opioid oxycodone use‐dependently inhibits the cardiac sodium channel Na_V1.5

Tramadol as a Voltage-Gated Sodium Channel Blocker of Peripheral Sodium Channels Na_v1.7 and Na_v1.5

Tramadol as a Voltage-Gated Sodium Channel Blocker of Peripheral Sodium Channels Na_v1.7 and Na_v1.5

Uncoupling sodium channel dimers restores the phenotype of a pain‐linked Na_v1.7 channel mutation