SNC80 and naltrindole modulate voltage-dependent sodium, potassium and calcium channels via a putatively delta opioid receptor-independent mechanism

Abstract

SNC80 was designed as a highly selective nonpeptide delta opioid receptor (DOR) agonist. Antidepressant-like and antinociceptive effects of this compound were demonstrated in animal models. Naltrindole was synthetized as a highly selective DOR antagonist. Its antitussive and antinociceptive effects were reported. Observed effects of SNC80 and naltrindole may be accompanied by changes in neuronal excitability including modulation of voltage-dependent ion channels. We investigated possible DOR-independent modulation of neuronal sodium, calcium and potassium currents by both agents. NG108-15 cells lacking expression of DOR protein were used as model of neuronal cells. Cells were differentiated into neuronal phenotype by exposure to dibutyryl cyclic-AMP (dbcAMP). Lack of DORs expression in NG108-15 cells and the presence of DOR expression in brain and neuronal cultures were demonstrated by Western blot analysis. Both SNC80 and naltrindole exerted low to moderate modulatory effects on voltage-dependent ion currents. SNC80 weakly inhibited sodium current, potentiated calcium current, and did not act on potassium channels. Naltrindole inhibited sodium current, did not act on calcium current and inhibited potassium current at a high concentration. Such effects should be taken into account when these compounds are used for investigation of DOR-mediated signaling pathways.

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

“…To test whether the effects of NAL could be unlinked to its binding to these opioid receptors, we further tested different types of central neurons, namely, NG108‐15 neuronal cells. This cell line has not been found to express these two types of opioid receptors although it may contain δ‐opioid receptors (Heiss, Ammer, & Eisinger, ; Moravcikova, Kralovicova, & Lacinova, ). Therefore, in a final set of experiments, any possible modifications of NAL on I Na in these cells were also tested.…”

The therapeutic potential of ultra-short-acting β-receptor antagonists in perioperative analgesic: Evidence from preclinical and clinical studies

“…There are many excitatory ion channels on the membranes of DRG primary afferent fibers, such as voltage-dependent Na + , K + , and Ca 2+ channels and the transient receptor potential channel. Blocking these channels in the DRG can reduce the transmission of pain signals and influence analgesia ( Moravcikova et al, 2018 ; Hermanns et al, 2019 ). Peripheral nociceptors are stimulated to produce action potentials, and afferent fibers of the DRG transmit these signals to the spinal cord dorsal horn.…”