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

Nalbuphine (NAL) is recognized as a mixer with the kappa-opioid receptor agonist and the mu-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 IC50 value of 1.9 mu M. 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 mu M) or naloxone (30 mu M) failed to modify its suppression of peak I-Na. Tefluthrin (Tef; 10 mu M), 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 IC50 value of 5.7 mu M, 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 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.