title: The effect of kappa-opioid receptor agonists on tetrodotoxin-resistant sodium channels in primary sensory neurons.
abstract: BACKGROUND
  A non-opioid receptor-mediated inhibition of sodium channels in dorsal root ganglia (DRGs) by kappa-opioid receptor agonists (kappa-ORAs) has been reported to contribute to the antinociceptive actions in animals and humans. In this study, we examined structurally diverse kappa-ORAs for their abilities to inhibit tetrodotoxin-resistant (TTX-r) sodium channels in adult rat DRGs.
  
  
  METHODS
  Whole-cell recordings of TTX-r sodium currents were performed on cultured adult rat DRGs. Structurally diverse kappa-ORAs were studied for their abilities to inhibit TTX-r sodium channels.
  
  
  RESULTS
  The racemic kappa-ORA, (+/-)U50,488, inhibited TTX-r sodium currents in a voltage-dependent manner, yielding IC(50) values of 49 and 8 muM, at prepulse potentials of -100 and -40 mV, respectively. Furthermore, we found that both the kappa-ORA U50,488 active enantiomer 1S,2S U50,488 and the inactive enantiomer 1R,2R U50,488 were equally potent inhibitors of TTX-r sodium currents. Structurally related kappa-ORAs, such as BRL 52537 and ICI 199,441 also inhibited TTX-r sodium currents. However, sodium channel inhibition and kappa-opioid receptor agonism have a distinct structure-activity relationship because another kappa-ORA (ICI 204,488) was inactive versus TTX-r sodium channels. We further investigated the sodium channel block of this class of compounds by studying (+/-)U50,488. (+/-)U50,488 was found to preferentially interact with the slow inactivated state of TTX-r sodium channels and to retard recovery from inactivation.
  
  
  CONCLUSIONS
  Our results suggest that TTX-r sodium channels can be inhibited by many kappa-ORAs via an opioid receptor-independent mechanism. Although the potency for sodium channel inhibition is typically much less than apparent affinity for opioid receptors, sodium channel block may still contribute to the antinociceptive effects of this class of compounds.
authors.affiliation: Icagen, Inc, Durham, North Carolina, USA. xin.su@medtronic.co
authors.forename: Xin
authors.initials: X
authors.lastname: Su
authors.forename: Neil A
authors.initials: NA
authors.lastname: Castle
authors.forename: Brett
authors.initials: B
authors.lastname: Antonio
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Roeloffs
authors.forename: James B
authors.initials: JB
authors.lastname: Thomas
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Krafte
authors.forename: Mark L
authors.initials: ML
authors.lastname: Chapman
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D011984:Sensory Receptor Cells / Q000187:drug effects*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013779:Tetrodotoxin / Q000494:pharmacology*
chemical_list: C454101:1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D010880:Piperidines; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C058468:ICI 199441; D013779:Tetrodotoxin; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer