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

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 IC₅₀ 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 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 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.