The G-protein biased partial κ opioid receptor agonist 6'-GNTI blocks hippocampal paroxysmal discharges without inducing aversion

Br J Pharmacol. 2016 Jun;173(11):1756-67. doi: 10.1111/bph.13474. Epub 2016 Apr 21.


Background and purpose: 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.

Experimental approach: 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.

Key results: 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.

Conclusions and implications: Our data provide the proof of principle that anticonvulsant/antiseizure and aversive effects of κ receptor activation can be pharmacologically separated in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Guanidines / pharmacology*
  • Heterotrimeric GTP-Binding Proteins / metabolism*
  • Hippocampus / drug effects*
  • Hippocampus / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Naltrexone / analogs & derivatives*
  • Naltrexone / pharmacology
  • Receptors, Opioid, kappa / agonists*
  • Seizures / drug therapy*
  • Seizures / psychology*


  • 6'-guanidinonaltrindole
  • Guanidines
  • Receptors, Opioid, kappa
  • Naltrexone
  • Heterotrimeric GTP-Binding Proteins