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Effectiveness of nalbuphine, a κ‐opioid receptor agonist and μ‐opioid receptor antagonist, in the inhibition of I Na , I K(M) , and I K(erg) unlinked to interaction with opioid receptors
Author(s) -
Liu YuanYuarn,
Hsiao HungTsung,
Wang Jeffery C.F.,
Liu YenChin,
Wu ShengNan
Publication year - 2019
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.21568
Subject(s) - agonist , chemistry , opioid receptor , (+) naloxone , antagonist , ic50 , nalbuphine , opioid , patch clamp , pharmacology , biophysics , endocrinology , receptor , medicine , biology , biochemistry , in vitro
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 ( I Na ) with an IC 50 value of 1.9 μM. It shifted the steady‐state inactivation curve of peak I Na to the hyperpolarized potential, suggesting that there is the voltage dependence of NAL‐mediated inhibition of peak I Na . In continued presence of NAL, subsequent application of either dynorphin A 1‐13 (1 μM) or naloxone (30 μM) failed to modify its suppression of peak I Na . Tefluthrin (Tef; 10 μM), a pyrethroid known to activate I Na , increased peak I Na with slowed current inactivation; however, further application of NAL suppressed Tef‐mediated suppression of peak I Na followed by an additional slowing of current inactivation. In addition, NAL suppressed the amplitude of M‐type K + current [ I K(M) ] with an IC 50 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 Ca 2+ ‐activated K + channels. In differentiated NG108‐15 neuronal cells, NAL also suppressed the peak I Na , and subsequent addition of Tef reversed NAL‐induced suppression of I Na . Our study highlights the evidence that in addition to modulate opioid receptors, NAL has the propensity to interfere with ionic currents including I Na and I K(M) , thereby influencing the functional activities of central neurons.