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NEUROPHARMACOLOGY

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

Departments of Internal Medicine (K.L., K.B.) and Pharmacology (S.K.J., G.F.G.), Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa

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 -opioid receptor agonists (-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 -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 -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.

Address correspondence to: Dr. G. F. Gebhart, Department of Pharmacology, BSB, The University of Iowa, Iowa City, IA 52242. E-mail: gf-gebhart{at}uiowa.edu