Effectiveness of nalbuphine, a κ-opioid receptor agonist and μ-opioid receptor antagonist, in the inhibition of I , I , and I 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 ) with an IC value of 1.9 μM. It shifted the steady-state inactivation curve of peak I to the hyperpolarized potential, suggesting that there is the voltage dependence of NAL-mediated inhibition of peak I . In continued presence of NAL, subsequent application of either dynorphin A (1 μM) or naloxone (30 μM) failed to modify its suppression of peak I . Tefluthrin (Tef; 10 μM), a pyrethroid known to activate I , increased peak I with slowed current inactivation; however, further application of NAL suppressed Tef-mediated suppression of peak I followed by an additional slowing of current inactivation. In addition, NAL suppressed the amplitude of M-type K current [I ] with an IC 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 -activated K channels. In differentiated NG108-15 neuronal cells, NAL also suppressed the peak I , and subsequent addition of Tef reversed NAL-induced suppression of I . Our study highlights the evidence that in addition to modulate opioid receptors, NAL has the propensity to interfere with ionic currents including I and I , thereby influencing the functional activities of central neurons.