dynorphins and Seizures

Anticonvulsant neuropeptides are best known for their ability to suppress seizures and modulate pain pathways. Galanin, neuropeptide Y, somatostatin, neurotensin, dynorphin, among others, have been validated as potential first-in-class anti-epileptic or/and analgesic compounds in animal models of epilepsy and pain, but their therapeutic potential extends to other neurological indications, including neurodegenerative and psychatric disorders. Disease-modifying properties of neuropeptides make them even more attractive templates for developing new-generation neurotherapeutics. Arguably, efforts to transform this class of neuropeptides into drugs have been limited compared to those for other bioactive peptides. Key challenges in developing neuropeptide-based anticonvulsants are: to engineer optimal receptor-subtype selectivity, to improve metabolic stability and to enhance their bioavailability, including penetration across the blood–brain barrier (BBB). Here, we summarize advances toward developing systemically active and CNS-penetrant neuropeptide analogs. Two main objectives of this review are: (1) to provide an overview of structural and pharmacological properties for selected anticonvulsant neuropeptides and their analogs and (2) to encourage broader efforts to convert these endogenous natural products into drug leads for pain, epilepsy and other neurological diseases.

Topics: Analgesics, Opioid; Anticonvulsants; Blood-Brain Barrier; Dynorphins; Epilepsy; Galanin; Molecular Structure; Nervous System Diseases; Neuropeptide Y; Neuropeptides; Neurotensin; Seizures; Sequence Homology, Amino Acid; Somatostatin

Epilepsy is a significant health problem. Despite the widespread use of both classic and newer pharmacological agents that target ion channels, amino acid transmission or receptors, there are numerous examples of mono- or polytherapy being ineffective. Seizures that are secondary to CNS infections are among the most refractory medically, and thus insult-specific agents are desirable. Recently, the study of the neuropharmacological actions of dynorphin in CNS viral injury has yielded new insights into epileptogenesis and epilepsy treatment. The opioid neuropeptide dynorphin modulates neuronal excitability in vitro in hippocampal slices and potentiates endogenous anti-ictal (i.e. protective) processes in animal models and humans. This work has renewed interest in the role of dysregulation of dynorphin in the pathogenesis of refractory seizures, including encephalitic seizures. The important role of dynorphin in epilepsy is also supported by new models of symptomatic epilepsies based on viral-induced seizures.

Topics: Animals; Central Nervous System Diseases; Disease Models, Animal; Dynorphins; Epilepsy; Hippocampus; Humans; Rats; Seizures

We have employed a molecular biological approach to study the dynamic status of hippocampal opioid peptides in response to seizures elicited by different experimental models, such as electroconvulsive shocks (ECS) and amygdaloid kindling. Both ECS- and kindling-induced seizures triggered an initial large release of enkephalin and dynorphin, but produced opposite long-term effects on the biosynthesis of these two peptides, an increase of enkephalin, and a drastic decrease of dynorphin. Electrical stimulation of the perforant pathway produced differential changes of enkephalin and dynorphin, which were identical to those of ECS and kindling. This finding confirmed our hypothesis that the perforant pathway was responsible for the mediation of ECS- and kindling-induced changes in opioid peptide turnover. Strongest evidence indicating a role for opioid peptides in mediating the expression of seizure-related behaviors was found using the kainic acid model, where we saw that hippocampal enkephalin was essential to the expression of kainic acid-induced wet dog shakes (a preconvulsive shaking behavior). Furthermore, it was found that the granular-mossy fiber pathway of the ventral, but not the dorsal, hippocampus was essential for the expression of this shaking behavior. However, destruction of the granular-mossy fiber pathway potentiated the seizures and hippocampal cell loss induced by kainic acid. This unexpected, yet extremely interesting, finding not only distinguished the roles of the granular-mossy fiber pathway in mediating wet dog shakes vs. convulsive seizures, but also challenged the dogma that this granular-mossy fiber pathway is essential for the expression of limbic seizures.

Topics: Afferent Pathways; Amygdala; Animals; Dynorphins; Electric Stimulation; Endorphins; Enkephalins; Gene Expression Regulation; Kindling, Neurologic; Limbic System; Nerve Fibers; Receptors, Opioid; Seizures; Synaptic Transmission

Topics: Animals; Cholecystokinin; Dynorphins; Endorphins; Enkephalins; Hippocampus; Neuropeptides; Protein Precursors; RNA, Messenger; Seizures

The evidence accumulated so far indicates that seizure activity exerts profound changes on the metabolism of opioid peptides in the hippocampus. Our data consistently show a large transient decrease in dynorphin and a modest decrease in enkephalin in the hippocampus following either a single ECS or KA injection. These initial reductions, which are indicative of increased release, may trigger the biosynthetic process of hippocampal opioids and result in an overproduction of the peptides seen in the rebound phase. However, the amount and timing of the rebound in enkephalin and dynorphin levels in response to repeated ECS, amygdaloid kindling, or KA differ drastically: a rapid and sustained increase in ME-LI follows all three treatments, in contrast to a slow recovery after a large and sustained decrease in DN-LI induced by repeated ECS and amygdaloid kindling. These results, which are unique to the hippocampus, suggest that differential mechanisms are operative in regulating the metabolism of these two opioid peptides in the hippocampus. It is likely that a well-coordinated regulation of hippocampal function can be achieved through the differential release of enkephalin and dynorphin and their subsequent interactions at different subtypes of opioid receptors following seizure activities. From a functional point of view, our data provide a neurochemical correlate of previous reports that brain opioid peptides may mediate ECS-induced behavioral alterations, such as changes in seizure threshold, postictal depression, and retrograde amnesia. The robust changes in the levels of opioid peptides in kindled rats, plus shortening of the kindling process by pretreatment with mu opioid antagonists, strongly suggest the involvement of brain opioid peptides in the development of kindling. Finally, these studies show clear evidence that enkephalin in the hippocampus is important in KA-induced WDS, a component of the opiate withdrawal syndrome in rodents (Isaacson and Lanthorn 1981). Further studies should help distinguish the regulatory mechanisms responsible for changes in opioid peptide metabolism during states of hyperexcitability in the hippocampal formation.

Topics: Amygdala; Animals; Behavior, Animal; Colchicine; Dynorphins; Electroshock; Endorphins; Enkephalin, Methionine; Hippocampus; Kainic Acid; Kindling, Neurologic; Seizures

In previous studies, we found that dynorphin exerts antiepileptic effect by activating the kappa opioid receptor (KOR). However, the role of neuronal autophagy in dynorphin/KOR-mediated antiepileptic is still unclear. This study aimed to investigate the molecular mechanism of dynorphin's antiepileptic effect by inhibiting autophagy and reducing neuronal apoptosis. Here, a pilocarpine-induced rat model of epilepsy was established and hippocampal neurons were treated with Mg

Topics: Animals; Anticonvulsants; Apoptosis; Autophagy; Biotin; Dynorphins; Epilepsy; Green Fluorescent Proteins; Mammals; Pilocarpine; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; RNA, Messenger; Seizures; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Epilepsy remains a major medical problem of unknown aetiology. Potentially, viruses can be environmental triggers for development of seizures in genetically vulnerable individuals. An estimated half of encephalitis patients experience seizures and approximately 4% develop status epilepticus. Epilepsy vulnerability has been associated with a dynorphin promoter region polymorphism or low dynorphin expression genotype, in man. In animals, the dynorphin system in the hippocampus is known to regulate excitability. The present study was designed to test the hypothesis that reduced dynorphin expression in the dentate gyrus of hippocampus due to periadolescent virus exposure leads to epileptic responses. Encephalitis produced by the neurotropic Borna disease virus in the rat caused epileptic responses and dynorphin to disappear via dentate granule cell loss, failed neurogenesis and poor survival of new neurons. Kappa opioid (dynorphin) agonists prevented the behavioural and electroencephalographic seizures produced by convulsant compounds, and these effects were associated with an absence of dynorphin from the dentate gyrus granule cell layer and upregulation of enkephalin in CA1 interneurons, thus reproducing a neurochemical marker of epilepsy, namely low dynorphin tone. A key role for kappa opioids in anticonvulsant protection provides a framework for exploration of viral and other insults that increase seizure vulnerability and may provide insights into potential interventions for treatment of epilepsy.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Blotting, Northern; Borna Disease; Cell Survival; Disease Models, Animal; Dynorphins; Electroencephalography; Encephalitis, Viral; Enkephalins; Hippocampus; Male; Naloxone; Narcotic Antagonists; Neurons; Rats; Rats, Inbred Lew; Receptors, Opioid, kappa; Seizures

The effect of intrastriatal administration of LY306740, a specific NK-1 receptor antagonist, on the behavior and changes in gene expression elicited by the psychomotor stimulant, amphetamine, was studied. Acute administration of amphetamine (2.5 mg/kg, i.p.) caused an increase in behavioral activity and preproenkephalin, preprodynorphin and substance P mRNA expression in the striatum. When amphetamine-treated rats were pretreated with LY306740 (35 and 20 nmoles per side, intrastriatally), there was a significant decrease in amphetamine-induced behavioral activity. Quantitative in situ hybridization histochemistry revealed that both concentrations of LY306740 significantly decreased amphetamine-induced mRNA expression of all three neuropeptides. These data indicate that striatal NK-1 receptors modulate amphetamine-induced behavior and mRNA expression of neuropeptides in the rat striatum.

Topics: Acetamides; Amphetamine; Animals; Area Under Curve; Behavior, Animal; Central Nervous System Stimulants; Corpus Striatum; Dynorphins; Gene Expression Regulation; In Situ Hybridization; Male; Microinjections; Motor Activity; Neurokinin-1 Receptor Antagonists; Neuropeptides; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures; Sleep; Substance P

While the morphometry of classical transmitter systems has been extensively studied, relatively little quantitative information is available on the subcellular distribution of peptidergic dense core vesicles (DCVs) within axonal arbors and terminals, and how distribution patterns change in response to neural activity. This study used correlated quantitative light and electron microscopic immunohistochemistry to examine dynorphin B-like immunoreactivity (dyn B-LI) in the rat hippocampal mossy fiber pathway before and after seizures. Forty-eight hours after seizures induced by two pentylenetetrazol injections, light microscopic dyn B-LI was decreased dorsally and increased ventrally. Ultrastructural examination indicated that, in the hilus of the dentate gyrus, these alterations resulted from changes that were almost entirely restricted to the profiles of the large mossy-like terminals formed by mossy fiber collaterals (which primarily contact spines), compared to the profiles of the smaller, less-convoluted terminals found on the same collaterals (which primarily contact aspiny dendritic shafts). Dorsally, mossy terminal profile labeled DCV (/DCV) density dropped substantially, while ventrally, both mossy terminal profile perimeter and /DCV density increased. In all terminal profile examined, /DCVs also were closely associated with the plasma membrane. Following seizures, there was a reorientation of /DCVs along the inner surface of mossy terminal profile membranes, in relation to the types of profiles adjacent to the membrane: in both the dorsal and ventral hilus, significantly fewer /DCVs were observed at sites apposed to dendrites, and significantly more were observed at sites apposed to spines. Thus, after seizures, changes specific to: (1) the dorsoventral level of the hippocampal formation, (2) the type of terminal, and (3) the type of profile in apposition to the portion of the terminal membrane examined were all observed. An explanation of these complex, interdependent alterations will probably require evoking multiple interrelated mechanisms, including selective prodynorphin synthesis, transport, and release.

Topics: Animals; Disease Models, Animal; Dynorphins; Endorphins; Immunohistochemistry; Linear Models; Male; Microscopy, Electron; Mossy Fibers, Hippocampal; Neuropeptides; Neurotransmitter Agents; Rats; Rats, Sprague-Dawley; Seizures

Prodynorphin mRNA and immunoreactive dynorphin A (ir-dynorphin A) levels were measured in different brain areas at various time points after amygdala kindled seizures. In the hippocampus, striatum and hypothalamus, prodynorphin mRNA levels were not significantly changed in kindled rats (killed 1 week after the last stimulus-evoked seizure), but they were significantly increased 1 h after seizures. The relative increase was the highest in the hippocampus (approximately 3-fold). In the brainstem, midbrain and cerebral cortex no changes in prodynorphin mRNA were detected in kindled rats, 1 h or 1 week after a kindled seizure. ir-Dynorphin A levels were significantly reduced in the hippocampus and in the striatum of kindled rats, as well as 5 and 60 min after kindled seizures, but they were increased back to control levels after 120 min. In the hypothalamus, ir-dynorphin A levels were significantly increased 120 min after a kindled seizure. ir-Dynorphin A levels were also significantly reduced in the brainstem and in the frontal, parietal and temporal cortex 120 min, but not 5 or 60 min, after a kindled seizure. Taken together, these data support the hypothesis that the dynorphinergic system is activated after amygdala kindled seizures, with different kinetics in different brain areas.

Topics: Amygdala; Animals; Blotting, Northern; Dynorphins; Enkephalins; Kindling, Neurologic; Male; Protein Precursors; Radioimmunoassay; Rats; Rats, Sprague-Dawley; RNA Probes; RNA, Messenger; Seizures

Rats were treated with escalating doses of cocaine until they experienced a convulsion and were euthanized 1 or 3 h after the last injection. Quantitative in situ hybridization histochemistry revealed that c-fos and zif/268 mRNAs were induced at 1 h in many limbic structures and declined 3 h after cocaine-induced convulsions. Preprodynorphin and preproenkephalin signals increased in many of the same structures 3 h, but not 1 h, after cocaine-induced convulsions.

Topics: Animals; Cocaine; Convulsants; DNA-Binding Proteins; Dynorphins; Early Growth Response Protein 1; Enkephalins; Gene Expression Regulation; Immediate-Early Proteins; In Situ Hybridization; Kindling, Neurologic; Limbic System; Male; Nerve Tissue Proteins; Protein Precursors; Proto-Oncogene Proteins c-fos; Rats; Seizures; Time Factors; Transcription Factors

It was shown in the experiments on rats that the repeated picrotoxin administration resulted in the kindling of generalized seizures. Generalized convulsions were followed by the development of either postictal depression or explosiveness. The injection of mu-opiate agonist met-enkephalin into hippocampus of kindled rats resulted in the increase in the severity of seizure reactions which were induced by picrotoxin and also in the increase in the number of animals with postictal explosiveness. The injection of dynorphin-A-1-13 (kappa-opiate agonist) into substantia nigra reticulata induced the locomotor depression which was like one in postictal period and resulted in the decrease of picrotoxin-induced seizures severity. It was concluded that mu-opiate system of hippocampus took part in the formation of generator of pathologically enhanced excitation in the structure during kindling and the development of seizure syndrome, providing also the postictal explosiveness. Kappa-opiate system of substantia nigra plays an important role in the activation of the antiepileptic system, limitation of seizures and the development of postictal depression.

Topics: Analgesics; Animals; Behavior, Animal; Drug Interactions; Dynorphins; Enkephalin, Methionine; Hippocampus; Kindling, Neurologic; Male; Narcotics; Peptide Fragments; Picrotoxin; Rats; Rats, Inbred Strains; Reaction Time; Receptors, Opioid; Seizures; Substantia Nigra

Rats chronically implanted with intrathecal catheters received intrathecal injections (10 microliters followed by 10 microliters saline flush) of either saline (n = 5), somatostatin (100 micrograms, n = 10), the somatostatin analog BIM 23003 (100 micrograms, n = 5), the somatostatin analog SMS 201-995 (100 micrograms, n = 5), the substance P analog [D-Pro2, D-Trp7,9] SP (10 micrograms, n = 10), or dynorphin A (1-17) (20 nmol, n = 8). These doses (somatostatin, substance P and dynorphin A) were selected based on previous studies in which they caused significant motor deficits. Effects on thermal cutaneous nociception, behavior, motor function and spinal cord histopathology were evaluated. All peptides caused severe neurotoxicity, evidenced by flaccid hind leg paralysis and lumbar spinal neuronal degeneration, which was accompanied by an inflammatory reaction in meninges and spinal gray matter. Histopathological changes had developed within 24 h after injection of somatostatin, substance P analog and dynorphin A, showing mild to severe neuronal degeneration and mild inflammatory responses in spinal cord and meninges. Significant antinociceptive effects, due to severe neurotoxic effects, were only observed following intrathecal injection of SMS 201-995 and the substance P analog. Potential neurotoxic mechanisms of the different peptides are discussed.

Topics: Animals; Dynorphins; Injections, Spinal; Male; Motor Activity; Neurotoxins; Octreotide; Pain; Peptide Fragments; Rats; Rats, Inbred Strains; Reference Values; Seizures; Somatostatin; Spinal Cord; Stereotyped Behavior; Substance P; Time Factors

The purpose of this study was to determine the role that dentate granule cells play in wet dog shakes (WDS), behavioral seizures, and hippocampal cell loss caused by systemic administration of kainic acid (KA). Rats were given bilateral injections of colchicine (COL) into the hippocampal formation to selectively lesion dentate granule cells. Two weeks later, they were injected subcutaneously with KA and were observed for WDS and seizures. Seizures were terminated with pentobarbital 2.5 hr after KA injection, and the rats were killed 48 hr later. The integrity of hippocampal cell populations and projections to the hippocampal formation from entorhinal cortex was assessed with radioimmunoassay and immunostaining for methionine-enkephalin (ME) and dynorphin (DYN) A, as well as with Timm and Nissl staining. Results indicate that COL injections eliminated KA-induced WDS, did not affect the latency to onset of seizures, and potentiated KA-induced cell loss in the CA3 region of hippocampus. COL lesions eliminated ME and DYN immunostaining of granule cells, but not ME immunostaining of entorhinal afferents to the dentate gyrus or Ammon's horn. These findings indicate that granule cells are an essential neuronal link in the expression of KA-induced WDS, but that seizures propagate along other pathways in the limbic system.

Topics: Animals; Behavior, Animal; Dynorphins; Enkephalin, Methionine; Granulocytes; Hippocampus; Immunohistochemistry; Kainic Acid; Male; Organ Size; Radioimmunoassay; Rats; Rats, Inbred F344; Seizures

Light microscopic immunocytochemical techniques were used to evaluate the influence of recurrent limbic seizure activity on the immunoreactivity for 3 neuropeptides--enkephalin, dynorphin, and cholecystokinin (CCK)--contained within the mouse hippocampal mossy fiber axonal system. Seizures were induced either by the placement of a small unilateral electrolytic lesion in the dentate gyrus hilus or by intraventricular injection of kainic acid. Both treatments induce epileptiform activity in hippocampus lasting several hours. Four days after either lesion placement or injection of 0.05-0.1 microgram kainic acid, immunoreactivity for all 3 peptides was altered throughout the intact mossy fiber system, bilaterally, but in distinctly different ways: enkephalin immunoreactivity (ENK-I) was dramatically elevated, dynorphin immunoreactivity was reduced, and CCK immunoreactivity (CCK-I) was either severely reduced or completely absent in the mossy fiber system. ENK-I was also clearly increased in other areas, including the lateral septum, the entorhinal cortex, and within the entorhinal (perforant path) efferents to temporal hippocampus. In contrast, the loss of CCK seemed restricted to the mossy fiber system in that immunostaining appeared normal in scattered hippocampal perikarya, within the dentate gyrus commissural system, as well as within other limbic structures. Four days after injections of 0.2 or 0.25 microgram kainic acid, mossy fiber ENK-I was greatly elevated, dynorphin immunoreactivity was reduced, but, unlike the situation with lower kainic acid doses, CCK-I was only modestly reduced in the mossy fibers and was clearly reduced in other hippocampal systems as well. These data indicate that epileptiform physiological activity differentially affects the regulation of 3 neuroactive peptides contained within the hippocampal mossy fiber system and suggest a mechanism through which seizurelike episodes can have a lasting influence on the operation of specific hippocampal circuitries.

Topics: Animals; Cholecystokinin; Dynorphins; Enkephalins; Hippocampus; Immunochemistry; Kainic Acid; Mice; Nerve Fibers; Seizures

Kainic acid (KA), an excitatory neurotoxin, was used as a tool to study the metabolism of hippocampal opioid peptides and their functional role in the expression of wet-dog shakes (WDS). A single intracerebral injection of KA (1 microgram/rat) caused recurrent motor seizures lasting 3-6 h. During the convulsive period, native Met5-enkephalin-like (ME-LI) and dynorphin A(1-8)-like (DYN-LI) immunoreactivities in hippocampus decreased by 31 and 63%, respectively. By 24 h after dosing, the hippocampal opioid peptides had returned to control levels, and by 48 h ME-LI had increased 270% and DYN-LI 150%. Immunocytochemical analysis revealed that ME-LI and Leu5-enkephalin-like (LE-LI) immunostaining in the mossy fibers of dentate granule cells and the perforant-temporoammonic pathway had decreased visibly by 6 h and had increased markedly by 48 h following KA. A visible decrease in DYN-LI in mossy fiber axons within 6 h was followed by a substantial increase at 48 h. To determine whether the increases in hippocampal ME-LI reflected changes in ME biosynthesis, levels of mRNA coding for preproenkephalin (mRNAenk) and cryptic ME-LI cleaved by enzyme digestion from preproenkephalin were measured. Following the convulsive period (6 h), mRNAenk was 400% of control, and by 24 h, cryptic ME-LI was 300% of control. Increases in native and cryptic ME-LI and in mRNAenk were also noted in entorhinal cortex, but not in hypothalamus or uninjected striatum. Our data suggest that KA-induced seizures cause an increase in ME release, followed by a compensatory increase in ME biosynthesis in the hippocampus and entorhinal cortex. Several lines of evidence from this study have suggested that hippocampal enkephalins are intimately related to KA-elicited WDS. The shaking behavior was attenuated by pretreatment with naloxone or antisera against [Met5]-enkephalin. We also observed that KA-induced WDS can be mimicked by intrahippocampal injection of enkephalin-related peptides. Furthermore, this study demonstrated that intact dentate granule cells are essential for KA- and enkephalin-induced WDS, since a colchicine injection into the ventral hippocampus, which selectively destroys granule cells, abolished this behavior.

Topics: Animals; Dynorphins; Endorphins; Enkephalin, Methionine; Hippocampus; Kainic Acid; Peptide Fragments; Rats; Seizures

Male Fischer-344 rats were given a single intrastriatal injection of kainic acid (KA; 1 microgram/rat), which caused recurrent motor seizures lasting 3-6 hr. During the convulsive period, native Met5-enkephalin-like (ME-LI) and dynorphin A (1-8)-like (DYN-LI) immunoreactivities in hippocampus decreased by 31 and 63%, respectively. By 24 hr after dosing, the hippocampal opioid peptides had returned to control levels, and by 48 hr ME-LI had increased 270% and DYN-LI 150%. Immunocytochemical analysis revealed that ME-LI and Leu5-enkephalin-like (LE-LI) immunostaining in the mossy fibers of dentate granule cells and the perforant-temporoammonic pathway had decreased visibly by 6 hr and had increased markedly by 48 hr following KA. A visible decrease in DYN-LI in mossy fiber axons within 6 hr was followed by a substantial increase by 48 hr. To determine whether the increases in hippocampal ME-LI reflected changes in ME biosynthesis, levels of mRNA coding for preproenkephalin (mRNAenk) and cryptic ME-LI cleaved by enzyme digestion from preproenkephalin were measured. Following the convulsive period (6 hr), mRNAenk was 400% of control, and by 24 hr, cryptic ME-LI was 300% of control. Increases in native and cryptic ME-LI and in mRNAenk were also noted in entorhinal cortex, but not in hypothalamus or uninjected striatum. Our data suggest that KA-induced seizures cause an increase in ME release, followed by a compensatory increase in ME biosynthesis in the hippocampus and entorhinal cortex.

Topics: Animals; Dynorphins; Enkephalin, Methionine; Enkephalins; Hippocampus; Histocytochemistry; Immunochemistry; Kainic Acid; Protein Precursors; Radioimmunoassay; Rats; Rats, Inbred F344; RNA, Messenger; Seizures

Dynorphin A (1-13) acutely elevated the seizure threshold (ST) to the convulsant flurothyl, and this action was not blocked by naloxone. Increases in ST were also observed following i.c.v. injections of the non-opioid fragment dynorphin A (3-13). Pretreatment with dynorphin A (1-13), but not dynorphin A (3-13), non-competitively blocked the anticonvulsant effect of the mu selective opioid DAGO. Furthermore, pretreatment with dynorphin A (1-13) antagonized the delta antagonist properties of naloxone or ICI 154,129 in this seizure model. Thus, in addition to its non-opioid anticonvulsant effects, dynorphin A (1-13) exhibits unique antagonist actions which appear to be specific for the active opioid fragment.

Topics: Animals; Anticonvulsants; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Flurothyl; Male; Naloxone; Peptide Fragments; Rats; Rats, Inbred Strains; Seizures

Ten daily electroconvulsive shocks (ECSs) caused a two-fold increase in (Met5)-enkephalin-like immunoreactivity (ME-LI) and an 80% increase in the level of mRNA coding for preproenkephalin A in the hypothalamus. These observations suggest that repeated ECSs increase the biosynthesis of hypothalamic ME. Ten daily ECSs also increased dynorphin A (1-8)-like immunoreactivity (DN-LI) in hypothalamus (45%) but not in frontal cortex. Unlike other brain regions, a 64% decrease of DN-LI was found in the hippocampus after 10 daily ECSs whereas a significant increase of ME-LI (40%) was observed. Furthermore, immunocytochemical studies revealed an increase of (Leu5)-enkephalin-like immunoreactivity in the perforant pathway and a decrease of DN-LI in the mossy fiber system of the hippocampus after 10 daily ECSs. These studies suggest that alterations in enkephalin and dynorphin in the limbic system may contribute to the behavioral changes observed after repeated ECSs.

Topics: Animals; Brain; Dynorphins; Electroshock; Enkephalin, Methionine; Hypothalamus; Male; Peptide Fragments; Protein Biosynthesis; Rats; Rats, Inbred F344; RNA, Messenger; Seizures

Kainic acid (KA) injected focally into the amygdala induced spontaneous recurrent motor seizures. One to 6 hr after the injection of KA, the hippocampal ir-dynorphin (ir-DYN) was significantly lowered whereas 24 hr after the injection it increased. The hippocampal level of ir-alpha-neoendorphin decreased 6 hr after KA injection, and reached the control level 24 hr after the injection. Chlordiazepoxide (5 mg/kg) and phenobarbital (40 mg/kg) blocked convulsions as well as the increase in the ir-DYN content. Cycloheximide (500 micrograms icv) also antagonized the increase in the hippocampal ir-DYN. The above findings suggest that hippocampal dynorphin-related peptides are released during the seizures and that these peptides may play a physiological role in the seizure phenomena and limbic excitability.

Topics: Amygdala; Animals; Dynorphins; Endorphins; Kainic Acid; Kinetics; Male; Protein Precursors; Radioimmunoassay; Rats; Rats, Inbred Strains; Seizures

The influence of amygdaloid kindling on brain and pituitary content of immunoreactive dynorphin (IR-DYN) and other opioid peptides was studied in rabbits. The kindling was very effective in increasing the hippocampal levels of IR-DYN, alpha-neoendorphin and Leu-enkephalin, but remained without any significant effect on the levels of IR-DYN and beta-endorphin in the majority of brain structures studied. The concentration of IR-DYN in the hippocampus remained at the control level throughout the development but was increased dramatically after completion of kindling. Biochemical alterations persisted for at least one month following the completion of kindling. The obtained results suggest that the hippocampal IR-DYN and related peptides may play some role in the maintenance of amygdaloid-kindled seizures.

Topics: Amygdala; Animals; Brain; Brain Chemistry; Dynorphins; Endorphins; Hippocampus; Kindling, Neurologic; Male; Pituitary Gland; Rabbits; Radioimmunoassay; Seizures; Spinal Cord; Tissue Distribution

The naturally epileptic Mongolian gerbil was used to investigate the epileptogenic properties of beta-endorphin, dynorphin, met-enkephalin and morphine. The results indicate that opioid induced "seizures" are different from naturally spontaneous seizures in the gerbil in respect to EEG recording and motor behavior. Evidence for a protective role in preventing seizures is also presented.

Topics: Animals; beta-Endorphin; Cerebral Cortex; Dynorphins; Endorphins; Enkephalin, Methionine; Epilepsy; Gerbillinae; Morphine; Naltrexone; Narcotics; Seizures