Premium
The G‐protein biased partial κ opioid receptor agonist 6′‐GNTI blocks hippocampal paroxysmal discharges without inducing aversion
Author(s) -
Zangrandi Luca,
Burtscher Johannes,
MacKay James P,
Colmers William F,
Schwarzer Christoph
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13474
Subject(s) - pharmacology , agonist , medicine , anticonvulsant , neuroscience , hippocampal formation , receptor , epilepsy , psychology
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 .