Arylacetamide κ-Opioid Receptor Agonists Produce a Tonic- and Use-Dependent Block of Tetrodotoxin-Sensitive and -Resistant Sodium Currents in Colon Sensory Neurons

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Abstract
We have previously reported that U50,488 [(trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide] enantiomers contribute to visceral antinociception by a nonopioid receptor-mediated blockade of sodium currents in colon sensory neurons. The present experiments were undertaken to examine the effect of arylacetamide κ-opioid receptor agonists (κ-ORAs) U50,488 and EMD 61,753 [(N-methyl-N-[1S)-1-phenyl)-2-(13S))-3-hydroxypyrrolidine-1-yl)-ethyl]-2,2-diphenylacetamide HCl] on tetrodotoxin-sensitive (TTX-S) and -resistant (TTX-R) sodium currents, and the mechanism of their sodium channel-blocking actions. Whole cell patch-clamp experiments were performed on colon sensory neurons from the S1 dorsal root ganglion identified by content of retrograde tracer 1.1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine metanesulfonate. The concentration-response curves of U50,488 and EMD 61,753, for tonic inhibition of total, TTX-S, and TTX-R sodium currents were similar (EC50 values for U50,488 and EMD 61,753 were 8.4 ± 1.69 and 1.2 ± 1.78 μM, respectively). In contrast, the peptide κ-ORA dynorphin was without effect in these experiments. U50,488 (10 μM) shifted the voltage dependence of steady-state inactivation curves for total, TTX-S, and TTX-R currents to more negative potentials. Inhibition was present at holding potentials of –100 to –20 mV. After the tonic block elicited by 10 μM U50,488, repetitive stimulation with 5-ms depolarizing pulses at a frequency of 3 Hz further enhanced the inhibition of total, TTX-R, and TTX-S currents by 43.8 ± 4.9, 46.2 ± 4.9, and 40 ± 3.2%, respectively. These results demonstrate that arylacetamide κ-ORAs nonselectively inhibit voltage-evoked sodium currents in a manner similar to local anesthetics, by enhancing closed-state inactivation and induction of use-dependent block.