title: Arylacetamide kappa-opioid receptor agonists produce a tonic- and use-dependent block of tetrodotoxin-sensitive and -resistant sodium currents in colon sensory neurons.
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 kappa-opioid receptor agonists (kappa-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 microM, respectively). In contrast, the peptide kappa-ORA dynorphin was without effect in these experiments. U50,488 (10 microM) 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 microM 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 kappa-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.
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Joshi
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lamb
authors.forename: K
authors.initials: K
authors.lastname: Bielefeldt
authors.forename: G F
authors.initials: GF
authors.lastname: Gebhart
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000081:Acetamides / Q000494:pharmacology; D000698:Analgesia; D000818:Animals; D003106:Colon / Q000166:cytology; D004347:Drug Interactions; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology*
chemical_list: D000081:Acetamides; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C092095:asimadoline