Kappa opioid receptor agonists suppress absence seizures in WAG/Rij rats

doi:10.1016/0304-3940(95)11303-E

Neuroscience Letters

Volume 186, Issues 2–3, 17 February 1995, Pages 131-134

https://doi.org/10.1016/0304-3940(95)11303-E Get rights and content

Abstract

Involvement of the κ opioid receptor in the regulation of epileptic activity was studied in WAG/Rij rats, a genetic model of absence epilepsy. I.c.v. administration of the κ agonists U50,488H {trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidynyl)-cyclohexyl]-benzeneacetamide}, U69,593 (5α,7α,8β)-(−)-N-methyl-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)benzeneacetamide) or PD117,302 ((±)-trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzo[b]thiophene-4-acetamide), 50 and 150 μg/5 μl each, dose-dependently decreased t the number and mean duration of spike wave discharges (SWD). Peripheral administration of U50,488H (10 and 30 mg/kg s.c.) also attenuated the seizure activity in this model. The specific κ opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 10 μg/5 μl i.c.v., 18 h before EEG registration) moderately increased the number of SWD, which suggests that endogenous opiods acting through κ receptors may tonically inhibit the seizure activity in these rats. In addition, the enhancement of an absence-like seizure activity induced by the specific μ opioid receptor agonist d-Ala²-N-methyl-Phe⁴-Gly⁵-ol-enkephalin (DAMGO, 0.7 μg/5 μl i.c.v.) was also attenuated in rats pretreated with U50,488H, U69,593 or PD117,302. These data indicate that activation of the κ opioid receptor exerts an inhibitory effect on absence-like seizure activity in WAG/Rij rats.

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Cited by (38)

Network analysis reveals a role of the hippocampus in absence seizures: The effects of a cannabinoid agonist
2023, Epilepsy Research
The role of the hippocampus (Hp) in absence epileptic networks and the effect of endocannabinoid system on this network remain enigmatic. Here, using adapted nonlinear Granger causality, we compared the differences in network strength in four intervals (baseline or interictal, preictal, ictal and postictal) in two hours before (Epoch 1) and six hours (epochs 2, 3 and 4) after the administration of three different doses of the endocannabinoid agonist WIN55,212–2 (WIN) or solvent. Local field potentials were recorded for eight hours in 23 WAG/Rij rats in the Frontal (FC), Parietal PC), Occipital Cortex (OC) and in the hippocampus (Hp). The four intervals were visually marked by an expert neurophysiologist and the strength of couplings between electrode pairs were calculated in both directions.
Ictally, a strong decrease in coupling strength was found between Hp and FC, as well as a large increase bidirectionally between PC and FC and unidirectionally from FC and PC to OC, and from FC to Hp over all epochs.
The highest dose of WIN increased the couplings strength from FC to Hp and from OC to PC during 4 and 2 hr respectively in all intervals, and decreased the FC to PC coupling strength postictally in epoch 2. A single rat showed generalized convulsive seizures after the highest dose: this rat shared not only coupling changes with the other rats in the same condition, but showed many more. WIN reduced SWD number in epoch 2 and 3, their mean duration increased in epochs 3 and 4.
Conclusions:during SWDs FC and PC are strongly coupled and drive OC, while at the same time the influence of Hp to FC is diminished. The first is in agreement with the cortical focus theory, the latter demonstrates an involvement of the hippocampus in SWD occurrence and that ictally the hippocampal control of the cortico-thalamo-cortical system is lost. WIN causes dramatic network changes which have major consequences for the decrease of SWDs, the occurrence of convulsive seizures, and the normal cortico-cortical and cortico-hippocampal interactions.
The effect of selective opioid receptor agonists and antagonists on epileptiform activity in morphine-dependent infant mice hippocampal slices
2017, International Journal of Developmental Neuroscience
Citation Excerpt :
It was found that DAMGO – a selective agonist of MOR – enhances absence epilepsy in rats, whereas the δ opioid receptor (DOR) agonist (DPDPE) showed no such effect. Interestingly, KOR agonists suppressed absence seizures in rats (Przewłocka et al., 1995). Some new facts confirm the putative anticonvulsant effects of dynorphin and other KOR agonists in self-sustaining status epilepticus in rats (Mazarati and Wasterlain, 2002) and ethanol withdrawal seizures in mice (Beadles-Bohling and Wiren, 2006).
Hippocampal slices of mouse brain were used to estimate how selective agonist and antagonist of opioid receptors alter Low-Mg⁺² artificial cerebrospinal fluid (LM-ACSF)-induced epileptiform activities in normal and morphine-dependent mice. Brain slices were obtained from control and morphine-dependent mice. The morphine-dependent group received morphine once a day for 5 consecutive days, and the control group received saline. All injections were administered subcutaneously (s.c) in a volume of 0.1 mL on postnatal days 14–18. Brain slices were perfused with LM-ACSF along with selective agonist and antagonist of μ, κ and δ opioid receptors. Changes in spike count per unit of time were used as indices to quantify the effects of LM-ACSF exposure in the slices. In both groups, DAMGO (selective μ opioid receptor agonist) and DPDPE (selective δ opioid receptor agonist) suppressed while Dyn-A (selective κ opioid receptor agonist) potentiated the epileptiform activity. Meanwhile, BFN-A (selective μ opioid receptor antagonist) recovered epileptiform activity in normal brain slices but not in morphine-dependent ones. NTI (selective δ opioid receptor antagonist) and nor-BNI (selective κ opioid receptor antagonist) decreased epileptiform activity. It seems that the excitatory effect of morphine on epileptiform activity was mediated through kappa receptors and its inhibitory effect was mediated via the mu receptor and, to a lesser degree, through the delta receptor. The pattern of effect was similar in normal and morphine-dependent slices, but the intensity of the effect was significantly stronger in normal mice. Finding of this study might be considered for further research and attention in epilepsy treatment.
Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development
2016, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Instead, a comparable age-related decrease in the PDYN mRNA levels was found in the frontal cortex and, to a lesser extent, in the striatum of both WAG/Rij and ACI rats (Lason et al., 1994b); this may be an independent additional factor facilitating the occurrence of SWDs, since the peptides derived from PDYN, interacting mainly with κ receptors, produce antiepileptic effects (Lason et al., 1994b; Przewlocka et al., 1995). Indeed, i.c.v. administration of U50,488H, which like PDYN-derived peptides, stimulates κ opioid receptors, decreased the number and mean duration of SWDs indicating that activation of the κ opioid receptor exerts an inhibitory effect on absence-like seizure activity in WAG/Rij rats (Przewlocka et al., 1995). κ receptor agonists not only act in a way opposite to μ receptor agonists (Lason et al., 1994a), but can also attenuate the μ agonist-induced increase of the number of SWDs; however, this receptor does not seem to be involved in the epileptogenesis process (Przewlocka et al., 1995).
The WAG/Rij rat model has recently gathered attention as a suitable animal model of absence epileptogenesis. This latter term has a broad definition encompassing any possible cause that determines the development of spontaneous seizures; however, most of, if not all, preclinical knowledge on epileptogenesis is confined to the study of post-brain insult models such as traumatic brain injury or post-status epilepticus models. WAG/Rij rats, but also synapsin 2 knockout, Kv7 current–deficient mice represent the first examples of genetic models where an efficacious antiepileptogenic treatment (ethosuximide) was started before seizure onset. In this review, we have critically reconsidered all articles published regarding WAG/Rij rats, from the perspective that the period before SWD onset is considered as the latent period. In our new theory on seizure development, it is proposed that genes might be considered as the initial ‘insult’ responsible for all plastic changes underpinning the development of spontaneous seizures. According to this idea, in WAG/Rij rats, genetic predisposition would lead to the development of abnormal bilateral cortical epileptic foci, which would then non-genetically stimulate the rest of the brain to rearrange networks in order to phenotypically develop seizures similarly to what happens during electrical kindling.
Sexual performance and precontact 50-kHz ultrasonic vocalizations in WAG/Rij rats: Effects of opioid receptor treatment
2014, Epilepsy and Behavior
WAG/Rij rats are genetically selected animals that model absence epilepsy in rats. Ultrasonic vocalizations and sexual behavior – both ethologically relevant markers of reward system functioning – are poorly described in this strain. The aim of our experiment was to investigate reward-dependent precontact 50-kHz vocalizations (PVs) and copulatory behavior as well as the effects of opioid receptor treatment on such behaviors in sexually experienced WAG/Rij males and rats from two control strains: Sprague–Dawley and Crl: Han Wistar. We analyzed the effects of the opioid receptor antagonist naltrexone (3 mg/kg) and the agonist morphine (1 mg/kg) administration. Additionally, we analyzed the initiation of copulation in sexually naïve males before drug treatment. A significantly lower number of sexually naïve WAG/Rij rats initiated copulation. Sexually experienced WAG/Rij males differed at the control session (after physiological saline treatment) compared with Sprague–Dawley rats: WAG/Rij rats displayed more 50-kHz precontact vocalizations and had longer mount and intromission latencies, longer ejaculation latency, longer postejaculatory latency to exploration, longer 22-kHz vocalization duration after ejaculation, and longer postejaculatory intromission latency. Compared with Crl: Han Wistar rats, WAG/Rij males displayed longer mount latency and shorter 22-kHz vocalization duration. Neither naltrexone nor morphine affected PVs in all groups. On the other hand, opioid receptor treatment differently influenced the number of intromissions required to achieve ejaculation and 22-kHz postejaculatory vocalization duration in WAG/Rij rats than in both control groups. This suggests functional differences in the opioid system in this strain. As a result of the number of males that initiated copulation as well as the number of intromissions to ejaculation and 22-kHz postejaculatory vocalizations which all depend on D1 receptor activation, we suggest that the proportion of opioid receptor to D1 receptors in WAG/Rij rats is different when compared with the control strains. The reward system of Wag/Rij rats with absence epilepsy is sensitive to social rewards (high level of precontact 50-kHz ultrasounds) although this strain displays a lower level of sexual motivation (longer mount latency) compared with other control strains. A lower number of sexually naïve rats initiating copulation and longer mount latency in sexually experienced males could suggest a moderate depressive-like syndrome in this strain of rats.
The involvement of limbic structures in typical and atypical absence epilepsy
2013, Epilepsy Research
Citation Excerpt :
This increased level of α-neoendorphin represents an increase in the level of prodynorphin and this might be involved in a neurochemical mechanism that could prevent the spreading of SWDs to the limbic system. This idea is based on outcomes of neurophysiological studies indicating that prodynorphin-derived peptides exert an inhibitory influence on hippocampal neurons (Nicoll et al., 1977) and that peptides derived from prodynorphin exert antiepileptic effects in WAG/Rij rats (Przewłocka et al., 1995). Besides the findings of this genetic model, in the GHB model of typical absence seizures, elevated levels of prodynorphin were found in the hippocampus, suggesting involvement of the limbic circuitry in this pharmacologic model (Lasoń et al., 1983).
Typical and atypical seizures of absence epilepsy are thought to be generated by a rhythmogenic interplay between the cortex and the thalamus. However, the question remains as to which other subcortical and extrathalamic structures are involved in the pathophysiology of typical and atypical absence epilepsy. Limbic structures are not thought to be involved in typical absence seizures, since in animal models and human patients there is no evidence for the occurrence of spike-and-wave discharges of absence seizures in the limbic regions. However, there are a number of observations from animal models of absence epilepsy that point to a possibly important link between absence seizure mechanisms and limbic structures. Atypical absence seizures are distinct in many ways from typical absence seizures although they bear considerable clinical, EEG, and pharmacological resemblance to typical absence seizures. The differences between typical and atypical seizures of absence epilepsy appear to be circuitry dependent. While both typical and atypical absence seizures involve the cortico-thalamo-cortical circuitry, they each engage different neuronal networks within that circuitry. This review examines the involvement of limbic structures in typical and atypical absence seizures, shows that limbic circuitry forms an integral component of the absence epilepsy network and concludes that further knowledge of this component is important for understanding the complex relationships involved in absence epilepsy.
30 years of dynorphins - New insights on their functions in neuropsychiatric diseases
2009, Pharmacology and Therapeutics
Since the first description of their opioid properties three decades ago, dynorphins have increasingly been thought to play a regulatory role in numerous functional pathways of the brain. Dynorphins are members of the opioid peptide family and preferentially bind to kappa opioid receptors. In line with their localization in the hippocampus, amygdala, hypothalamus, striatum and spinal cord, their functions are related to learning and memory, emotional control, stress response and pain. Pathophysiological mechanisms that may involve dynorphins/kappa opioid receptors include epilepsy, addiction, depression and schizophrenia. Most of these functions were proposed in the 1980s and 1990s following histochemical, pharmacological and electrophysiological experiments using kappa receptor-specific or general opioid receptor agonists and antagonists in animal models. However, at that time, we had little information on the functional relevance of endogenous dynorphins. This was mainly due to the complexity of the opioid system. Besides actions of peptides from all three classical opioid precursors (proenkephalin, prodynorphin, proopiomelanocortin) on the three classical opioid receptors (delta, mu and kappa), dynorphins were also shown to exert non-opioid effects mainly through direct effects on NMDA receptors. Moreover, discrepancies between the distribution of opioid receptor binding sites and dynorphin immunoreactivity contributed to the difficulties in interpretation. In recent years, the generation of prodynorphin- and opioid receptor-deficient mice has provided the tools to investigate open questions on network effects of endogenous dynorphins.
This article examines the physiological, pathophysiological and pharmacological implications of dynorphins in the light of new insights in part obtained from genetically modified animals.

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Kappa opioid receptor agonists suppress absence seizures in WAG/Rij rats

Abstract

Epilepsy Res.

Brain Res. Rev.

Neuropharmacology

Eur. J. Pharmacol.

Neuropeptides

Neuropharmacology

Neuropeptides

Life Sci.

Life Sci.

Life Sci.