Effectiveness of nalbuphine, a κ-opioid receptor agonist and μ-opioid receptor antagonist, in the inhibition of INa, IK(M), and IK(erg) unlinked to interaction with opioid receptors

Yuan Yuarn Liu, Hung Tsung Hsiao, Jeffery C.F. Wang, Yen Chin Liu, Sheng-Nan Wu

Research output: Contribution to journalArticle

Abstract

Nalbuphine (NAL) is recognized as a mixer with the κ-opioid receptor agonist and the μ-opioid receptor antagonist. However, whether this drug causes any modifications in neuronal ionic currents is unclear. The effects of NAL on ionic currents in mHippoE-14 hippocampal neurons were investigated. In the whole-cell current recordings, NAL suppressed the peak amplitude of voltage-gated Na+ current (INa) with an IC50 value of 1.9 μM. It shifted the steady-state inactivation curve of peak INa to the hyperpolarized potential, suggesting that there is the voltage dependence of NAL-mediated inhibition of peak INa. In continued presence of NAL, subsequent application of either dynorphin A1-13 (1 μM) or naloxone (30 μM) failed to modify its suppression of peak INa. Tefluthrin (Tef; 10 μM), a pyrethroid known to activate INa, increased peak INa with slowed current inactivation; however, further application of NAL suppressed Tef-mediated suppression of peak INa followed by an additional slowing of current inactivation. In addition, NAL suppressed the amplitude of M-type K+ current [IK(M)] with an IC50 value of 5.7 μM, while it slightly suppressed erg-mediated and delayed-rectifier K+ currents. In the inside-out current recordings, NAL failed to modify the activity of large-conductance Ca2+-activated K+ channels. In differentiated NG108-15 neuronal cells, NAL also suppressed the peak INa, and subsequent addition of Tef reversed NAL-induced suppression of INa. Our study highlights the evidence that in addition to modulate opioid receptors, NAL has the propensity to interfere with ionic currents including INa and IK(M), thereby influencing the functional activities of central neurons.

Original languageEnglish
JournalDrug Development Research
DOIs
Publication statusPublished - 2019 Jan 1

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Nalbuphine
Narcotic Antagonists
Opioid Receptors
Inhibitory Concentration 50
Neurons
Calcium-Activated Potassium Channels
Dynorphins
Pyrethrins
Patch-Clamp Techniques
Naloxone

All Science Journal Classification (ASJC) codes

  • Drug Discovery

Cite this

@article{bc80f057a7e94426a709292e5d5e4d11,
title = "Effectiveness of nalbuphine, a κ-opioid receptor agonist and μ-opioid receptor antagonist, in the inhibition of INa, IK(M), and IK(erg) unlinked to interaction with opioid receptors",
abstract = "Nalbuphine (NAL) is recognized as a mixer with the κ-opioid receptor agonist and the μ-opioid receptor antagonist. However, whether this drug causes any modifications in neuronal ionic currents is unclear. The effects of NAL on ionic currents in mHippoE-14 hippocampal neurons were investigated. In the whole-cell current recordings, NAL suppressed the peak amplitude of voltage-gated Na+ current (INa) with an IC50 value of 1.9 μM. It shifted the steady-state inactivation curve of peak INa to the hyperpolarized potential, suggesting that there is the voltage dependence of NAL-mediated inhibition of peak INa. In continued presence of NAL, subsequent application of either dynorphin A1-13 (1 μM) or naloxone (30 μM) failed to modify its suppression of peak INa. Tefluthrin (Tef; 10 μM), a pyrethroid known to activate INa, increased peak INa with slowed current inactivation; however, further application of NAL suppressed Tef-mediated suppression of peak INa followed by an additional slowing of current inactivation. In addition, NAL suppressed the amplitude of M-type K+ current [IK(M)] with an IC50 value of 5.7 μM, while it slightly suppressed erg-mediated and delayed-rectifier K+ currents. In the inside-out current recordings, NAL failed to modify the activity of large-conductance Ca2+-activated K+ channels. In differentiated NG108-15 neuronal cells, NAL also suppressed the peak INa, and subsequent addition of Tef reversed NAL-induced suppression of INa. Our study highlights the evidence that in addition to modulate opioid receptors, NAL has the propensity to interfere with ionic currents including INa and IK(M), thereby influencing the functional activities of central neurons.",
author = "Liu, {Yuan Yuarn} and Hsiao, {Hung Tsung} and Wang, {Jeffery C.F.} and Liu, {Yen Chin} and Sheng-Nan Wu",
year = "2019",
month = "1",
day = "1",
doi = "10.1002/ddr.21568",
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T1 - Effectiveness of nalbuphine, a κ-opioid receptor agonist and μ-opioid receptor antagonist, in the inhibition of INa, IK(M), and IK(erg) unlinked to interaction with opioid receptors

AU - Liu, Yuan Yuarn

AU - Hsiao, Hung Tsung

AU - Wang, Jeffery C.F.

AU - Liu, Yen Chin

AU - Wu, Sheng-Nan

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Nalbuphine (NAL) is recognized as a mixer with the κ-opioid receptor agonist and the μ-opioid receptor antagonist. However, whether this drug causes any modifications in neuronal ionic currents is unclear. The effects of NAL on ionic currents in mHippoE-14 hippocampal neurons were investigated. In the whole-cell current recordings, NAL suppressed the peak amplitude of voltage-gated Na+ current (INa) with an IC50 value of 1.9 μM. It shifted the steady-state inactivation curve of peak INa to the hyperpolarized potential, suggesting that there is the voltage dependence of NAL-mediated inhibition of peak INa. In continued presence of NAL, subsequent application of either dynorphin A1-13 (1 μM) or naloxone (30 μM) failed to modify its suppression of peak INa. Tefluthrin (Tef; 10 μM), a pyrethroid known to activate INa, increased peak INa with slowed current inactivation; however, further application of NAL suppressed Tef-mediated suppression of peak INa followed by an additional slowing of current inactivation. In addition, NAL suppressed the amplitude of M-type K+ current [IK(M)] with an IC50 value of 5.7 μM, while it slightly suppressed erg-mediated and delayed-rectifier K+ currents. In the inside-out current recordings, NAL failed to modify the activity of large-conductance Ca2+-activated K+ channels. In differentiated NG108-15 neuronal cells, NAL also suppressed the peak INa, and subsequent addition of Tef reversed NAL-induced suppression of INa. Our study highlights the evidence that in addition to modulate opioid receptors, NAL has the propensity to interfere with ionic currents including INa and IK(M), thereby influencing the functional activities of central neurons.

AB - Nalbuphine (NAL) is recognized as a mixer with the κ-opioid receptor agonist and the μ-opioid receptor antagonist. However, whether this drug causes any modifications in neuronal ionic currents is unclear. The effects of NAL on ionic currents in mHippoE-14 hippocampal neurons were investigated. In the whole-cell current recordings, NAL suppressed the peak amplitude of voltage-gated Na+ current (INa) with an IC50 value of 1.9 μM. It shifted the steady-state inactivation curve of peak INa to the hyperpolarized potential, suggesting that there is the voltage dependence of NAL-mediated inhibition of peak INa. In continued presence of NAL, subsequent application of either dynorphin A1-13 (1 μM) or naloxone (30 μM) failed to modify its suppression of peak INa. Tefluthrin (Tef; 10 μM), a pyrethroid known to activate INa, increased peak INa with slowed current inactivation; however, further application of NAL suppressed Tef-mediated suppression of peak INa followed by an additional slowing of current inactivation. In addition, NAL suppressed the amplitude of M-type K+ current [IK(M)] with an IC50 value of 5.7 μM, while it slightly suppressed erg-mediated and delayed-rectifier K+ currents. In the inside-out current recordings, NAL failed to modify the activity of large-conductance Ca2+-activated K+ channels. In differentiated NG108-15 neuronal cells, NAL also suppressed the peak INa, and subsequent addition of Tef reversed NAL-induced suppression of INa. Our study highlights the evidence that in addition to modulate opioid receptors, NAL has the propensity to interfere with ionic currents including INa and IK(M), thereby influencing the functional activities of central neurons.

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U2 - 10.1002/ddr.21568

DO - 10.1002/ddr.21568

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JO - Drug Development Research

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SN - 0272-4391

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