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

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.

Nalbuphine attenuates morphine‐induced scratching by inhibiting PKCβ‐dependent microglial activation and p38 phosphorylation in male mice

“…Recently, a study found that in addition to modulating opioid receptor, nalbuphine can also suppress the peak amplitude of voltage‐gated Na + current (INa) and the amplitude of M‐type K + current [IK(M)], thereby influencing the functional activities of central neurons (Liu et al, 2019). Whether this mechanism is also involved in nalbuphine‐inhibited MIS deserves further exploration.…”

Nalbuphine May Be Superior to Sufentanil in Relieving Postcesarean Uterine Contraction Pain in Multiparas: A Retrospective Cohort Study

“…48 Nalbuphine may alleviate visceral hyperalgesia by inactivating primary sensory afferent-located voltage-gated sodium and potassium channels. 49 Previous animal studies have proved that visceral hyperalgesia can be alleviated by Nalbuphine. 50,51 That may explain, at least partly, why Nalbuphine showed superior analgesic effects in multipara after CS.…”

Investigation of the Median Effective Concentration of Ropivacaine Combined with Nalbuphine as Epidural Analgesia

“…Low-concentration ropivacaine is used in labor analgesic drug dosing regimens, and it is often used in combination with opioids in order to further improve analgesic efficacy. It has been suggested that nalbuphine is a partial antagonist of mu (μ) receptors, an agonist of gamma (γ) receptors, highly selective for kappa (κ) receptors in the brain and spinal cord, highly effective in suppressing visceral pain, reducing opioid concentrations in labor analgesia, and improving maternal adverse effects [10,11] . Nalbuphine combined with ropivacaine analgesic regimens have been reported [12] but studies on the effect of different concentrations of nalbuphine on labor analgesia in combined regimens are scarce.…”