Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 173, Issue 11, Pages 1756-1767Publisher
WILEY
DOI: 10.1111/bph.13474
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Funding
- Austrian Science Fund (FWF) [W1206-B05, I-977-B24]
- Austrian Science Fund (FWF) [W1206, I977] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [I 977] Funding Source: researchfish
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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 kappa opioid receptor (kappa receptor) agonists have been proposed since the 1980s. However, their clinical use was hampered by dysphoric side effects. Recently, G-protein biased kappa receptor agonists were developed, suggesting reduced aversive effects. EXPERIMENTAL APPROACH We investigated the effects of the kappa receptor agonist U-50488H and the G-protein biased partial kappa 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 kappa 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 kappa receptor activation can be pharmacologically separated in vivo.
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