Kappa opioid receptor activation blocks progressive neurodegeneration after kainic acid injection

Abstract

We recently demonstrated that endogenous prodynorphin-derived peptides mediate anticonvulsant, antiepileptogenic and neuroprotective effects via kappa opioid receptors (KOP). Here we show acute and delayed neurodegeneration and its pharmacology after local kainic acid injection in prodynorphin knockout and wild-type mice and neuroprotective effect(s) of KOP activation in wild-type mice. Prodynorphin knockout and wild-type mice were injected with kainic acid (3 nmoles in 50 nl saline) into the stratum radiatum of CA1 of the right dorsal hippocampus. Knockout mice displayed significantly more neurodegeneration of pyramidal cells and interneurons than wild-type mice 2 days after treatment. This phenotype could be mimicked in wild-type animals by treatment with the KOP antagonist GNTI and rescued in knockout animals by the KOP agonist U-50488. Minor differences in neurodegeneration remained 3 weeks after treatment, mostly because of higher progressive neurodegeneration in wild-type mice compared with prodynorphin-deficient animals. In wild-type mice progressive neurodegeneration, but not acute neuronal loss, could be mostly blocked by U-50488 treatment. Our data suggest that endogenous prodynorphin-derived peptides sufficiently activate KOP receptors during acute seizures, and importantly in situations of reduced dynorphinergic signaling-like in epilepsy-the exogenous activation of KOP receptors might also have strong neuroprotective effects during excitotoxic events.

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

“…Treatment of mice injected with kainic acid with the κ receptor agonist U‐50488H results in reduced neuronal loss (Schunk et al , ) and reduces hippocampal paroxysmal discharges (this study). However, general κ receptor agonists induce dysphoria in humans (Barber and Gottschlich, ) and aversive effects in mice (Land et al , ).…”

“…Various selective κ receptor agonists applied through different routes yielded time‐dependent and dose‐dependent effects similar to those upon treatment with phenytoin or phenobarbital in models of epilepsy (see Simonato and Romualdi, ). We recently demonstrated that the activation of κ receptors promotes the survival of hippocampal and amygdala neurons subsequent to the acute phase after unilateral injection of kainic acid in mice (Schunk et al , ).…”

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

“…This phenotype could be entirely rescued by kappa receptor-specific agonist while a delta-specific agonist decreased seizure threshold in both wild-type and knockout mice [141]. Moreover prodynorphin knockout mice showed faster seizure onset and a prolonged time of seizure activity after kainate injection, which was accompanied by an increased extent of neuronal loss in the hippocampus [142]. The involvement of dynorphin in the etiology of epilepsy was also strengthened by a functional polymorphism in the prodynorphin gene promotor associated with temporal lobe epilepsy.…”

Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependence

“…Thus, the net effect would be decreased signaling via the KOR. Partial agonists at the KOR, as opposed to antagonists, could be of special importance in the alcohol dependence field because of evidence showing that withdrawal in alcohol dependent individuals can be characterized by increased seizure probability and that KOR stimulation in the hippocampus protects against the production of certain types of seizures (Loacker et al, 2007; Schunk et al, 2010)…”