Endogenous dynorphin in epileptogenesis and epilepsy: anticonvulsant net effect via kappa opioid receptors

Loacker, Stephan; Sayyah, Mohammad; Wittmann, Walter; Herzog, Herbert; Schwarzer, Christoph

doi:10.1093/brain/awl384

Cited by 117 publications

(106 citation statements)

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“…These mice displayed a reduced seizure threshold in response to pentylenetetrazole. 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].…”

Section: Dynorphin and Enkephalinmentioning

confidence: 97%

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre-and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have been implicated in epilepsy and many of them are considered to have endogenous neuroprotective actions. Neuropeptides, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic substances. Hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin-releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Oral application of neuropeptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of neuropeptides within the central nervous system will also be discussed.

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Section: Dynorphin and Enkephalinmentioning

confidence: 97%

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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“…Dynorphin knockout mice (Dyn−/−) and neuropeptide Y knockout mice (NPY−/−) were generated and maintained as previously published (Loacker et al, 2007 andKarl et al, 2008). The dynorphin knockout leads to deletion of the entire prodynorphin gene including the initiation start codon, thereby eliminating all six potential dynorphin peptides.…”

Section: Animalsmentioning

confidence: 99%

The endogenous opioid dynorphin is required for normal bone homeostasis in mice

et al. 2012

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Chronic opiate usage, whether prescribed or illicit, has been associated with changes in bone mass and is a recognized risk factor for the development of osteoporosis; however, the mechanism behind this effect is unknown. Here we show that lack of dynorphin, an endogenous opioid, in mice (Dyn−/−), resulted in a significantly elevated cancellous bone volume associated with greater mineral apposition rate and increased resorption indices. A similar anabolic phenotype was evident in bone of mice lacking dynorphin's cognate receptor, the kappa opioid receptor. Lack of opioid receptor expression in primary osteoblastic cultures and no change in bone cell function after dynorphin agonist treatment in vitro indicates an indirect mode of action. Consistent with a hypothalamic action, central dynorphin signaling induces extracellular signal-regulated kinase (ERK) phosphorylation and c-fos activation of neurons in the arcuate nucleus of the hypothalamus (Arc). Importantly, this signaling also leads to an increase in Arc NPY mRNA expression, a change known to decrease bone formation. Further implicating NPY in the skeletal effects of dynorphin, Dyn−/−/NPY−/− double mutant mice showed comparable increases in bone formation to single mutant mice, suggesting that dynorphin acts upstream of NPY signaling to control bone formation. Thus the dynorphin system, acting via NPY, may represent a pathway by which higher processes including stress, reward/addiction and depression influence skeletal metabolism. Moreover, understanding of these unique interactions may enable modulation of the adverse effects of exogenous opioid treatment without directly affecting analgesic responses.

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“…For example, the administration of nonpeptidic ␦-opioid agonists is known to cause seizure in laboratory animals (Jutkiewicz, 2006), whereas activation of -opioid receptors may exert anticonvulsant activity (Loacker et al, 2007). In this context, the higher potency and efficacy of amoxapine at ␦-versus -opioid receptors may correlate with the observed greater risk of seizure associated with amoxapine overdose, compared with other antidepressants (Litovitz and Troutman, 1983).…”

Section: Downloaded Frommentioning

confidence: 99%

Direct Agonist Activity of Tricyclic Antidepressants at Distinct Opioid Receptor Subtypes

Onali¹,

Dedoni²,

Olianas³

2009

J Pharmacol Exp Ther

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Tricyclic antidepressants (TCAs) have been reported to interact with the opioid system, but their pharmacological activity at opioid receptors has not yet been elucidated. In the present study, we investigated the actions of amoxapine, amitriptyline, nortriptyline, desipramine, and imipramine at distinct cloned and native opioid receptors. In Chinese hamster ovary (CHO) cells expressing ␦-opioid receptors (CHO/DOR), TCAs displaced [3H]naltrindole binding and stimulated guanosine 5Ј-O-(3-[35 S]thio)triphosphate ([ 35 S]GTP␥S) binding at micromolar concentrations with amoxapine displaying the highest potency and efficacy. Amoxapine and amitriptyline inhibited cyclic AMP formation and induced the phosphorylation of signaling molecules along the extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3 kinase pathways. Amoxapine also activated ␦-opioid receptors in rat dorsal striatum and nucleus accumbens and human frontal cortex. In CHO cells expressing -opioid receptors (CHO/KOR), TCAs, but not amoxapine, exhibited higher receptor affinity and more potent stimulation of [35 S]GTP␥S binding than in CHO/DOR and effectively inhibited cyclic AMP accumulation. Amitriptyline regulated ERK1/2 phosphorylation and activity in CHO/KOR and C6 glioma cells endogenously expressing -opioid receptors, and this effect was attenuated by the -opioid antagonist nor-binaltorphimine. In rat nucleus accumbens, amitriptyline slightly inhibited adenylyl cyclase activity and counteracted the inhibitory effect of the full agonist trans-(Ϫ) -3,4dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50,488). At the cloned -opioid receptor, TCAs showed low affinity and no significant agonist activity. These results show that TCAs differentially regulate opioid receptors with a preferential agonist activity on either ␦ or subtypes and suggest that this property may contribute to their therapeutic and/or side effects.Although the inhibition of presynaptic reuptake of monoamines is considered to be the primary mechanism of action of tricyclic antidepressants (TCAs), it is well established that these drugs can act on multiple molecular targets by affecting the activity of distinct neurotransmitter receptor systems and ion channels (Baldessarini, 2006). These secondary actions have been generally related to TCAs' adverse side effects, although some of them have been proposed to contribute to the therapeutic activity.An interaction with the opioid system has long been shown to be involved in the analgesic and mood-elevating effects of TCAs. A number of studies have reported that the antinociceptive effects of TCAs are reversed by opioid receptor antagonists (Biegon and Samuel, 1980;Gray et al., 1998;Marchand et al., 2003; Benbouzid et al., 2008a,b) and that TCAs potentiate morphine-induced analgesia both in animals (Hamon et al., 1987) and in humans (Micó et al., 2006). In animal behavioral tests predictive of antidepressant effects in humans, such as the forced swimming and learned helplessness tests, th...

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Endogenous dynorphin in epileptogenesis and epilepsy: anticonvulsant net effect via kappa opioid receptors

Cited by 117 publications

References 50 publications

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

The endogenous opioid dynorphin is required for normal bone homeostasis in mice

Direct Agonist Activity of Tricyclic Antidepressants at Distinct Opioid Receptor Subtypes

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