title: The G-protein biased partial κ opioid receptor agonist 6'-GNTI blocks hippocampal paroxysmal discharges without inducing aversion.
abstract: With a prevalence of 1-2%, epilepsies belong to the most frequent neurological diseases worldwide. Although antiepileptic drugs are available since several decades, the incidence of patients that are refractory to medication is still over 30%. Antiepileptic effects of κ opioid receptor (κ receptor) agonists have been proposed since the 1980s. However, their clinical use was hampered by dysphoric side effects. Recently, G-protein biased κ receptor agonists were developed, suggesting reduced aversive effects.
  
  
  
  We investigated the effects of the κ receptor agonist U-50488H and the G-protein biased partial κ receptor agonist 6'-GNTI in models of acute seizures and drug-resistant temporal lobe epilepsy and in the conditioned place avoidance (CPA) test. Moreover, we performed slice electrophysiology to understand the functional mechanisms of 6'-GNTI.
  
  
  
  As previously shown for U-50488H, 6'-GNTI markedly increased the threshold for pentylenetetrazole-induced seizures. All treated mice displayed reduced paroxysmal activity in response to U-50488H (20 mg·kg(-1) ) or 6'-GNTI (10-30 nmoles) treatment in the mouse model of intra-hippocampal injection of kainic acid. Single cell recordings on hippocampal pyramidal cells revealed enhanced inhibitory signalling as potential mechanisms causing the reduction of paroxysmal activity. Effects of 6'-GNTI were blocked in both seizure models by the κ receptor antagonist 5'-GNTI. Moreover, 6'-GNTI did not induce CPA, a measure of aversive effects, while U-50488H did.
  
  
  
  Our data provide the proof of principle that anticonvulsant/antiseizure and aversive effects of κ receptor activation can be pharmacologically separated in vivo.
authors.affiliation: Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Luca
authors.initials: L
authors.lastname: Zangrandi
authors.affiliation: Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Burtscher
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, AB, Canada.
authors.forename: James P
authors.initials: JP
authors.lastname: MacKay
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, AB, Canada.
authors.forename: William F
authors.initials: WF
authors.lastname: Colmers
authors.affiliation: Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schwarzer
mesh_terms: D000818:Animals; D006146:Guanidines / Q000494:pharmacology*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D012640:Seizures / Q000188:drug therapy* / Q000523:psychology*
chemical_list: C503316:6'-guanidinonaltrindole; D006146:Guanidines; D017473:Receptors, Opioid, kappa; D009271:Naltrexone; D020962:Heterotrimeric GTP-Binding Proteins