naltrindole and Seizures

Social isolation stress (SIS) as a chronic model of early-life stress could induce proconvulsant effects in mice. In the current study, we evaluated the role of opioid receptors (OPRs) agonists and antagonists in pro-conversant effects of SIS and the common pathway between delta-opioid receptors (DORs) and nitric oxide (NO) in stress-induced seizure. For reaching to this goal, we used pentylenetetrazol (PTZ) model of clonic-seizure to measure seizure threshold and administrated selective and non-selective OPRs agonists and antagonists in both social condition (SC) and isolated condition (IC) animals. In the next step, we administrated sub effective dose of naltrindole (NLT, 0.3 mg/kg) with sub-effective doses of nitric oxide synthesis (NOS) inhibitors including L-NAME (10 mg/kg), aminoguanidine (50 mg/kg) and 7-NI (15 mg/kg). Also, we co-administrated sub-effective dose of SNC80 (0.5 mg/kg) with sub-effective dose of l-arg (25 mg/kg) to assess the seizure threshold. In addition, we measured nitrite levels of hippocampus following administration of mentioned drugs in both SC and IC mice. Our findings showed that L-NAME and 7-NI (but not AG) increased anti-convulsant activity of NLT and l-arg increased proconvulsant effects of SNC80 in IC animals. Nitrite assay showed that co-administration of NLT plus sub-effective doses of L-NAME and 7-NI (but not AG) decreased and co-administration of SNC80 with sub-effective dose of l-arg increased nitrite levels of hippocampus in IC mice. This study suggests the role of n-NOS in anti-convulsant effects of NLT and pro-convulsant effects of SNC80 in stress-induced seizure.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Hippocampus; Male; Mice; Naltrexone; Narcotic Antagonists; Nitric Oxide; Nitric Oxide Synthase Type I; Pentylenetetrazole; Receptors, Opioid, delta; Seizures; Signal Transduction; Social Isolation; Stress, Psychological

This study was designed to investigate whether delta opioid receptor (DOR) is involved in the neuroprotective effect induced by hypoxic preconditioning (HPC) in the asphyxial cardiac arrest (CA) rat model. Twenty-four hours after the end of 7-day HPC, the rats were subjected to 8-min asphyxiation and resuscitated with a standardized method. In the asphyxial CA rat model, HPC improved the neurological deficit score (NDS), inhibited neuronal apoptosis, and increased the number of viable hippocampal CA1 neurons at 24 h, 72 h, or 7 days after restoration of spontaneous circulation (ROSC); however, the above-mentioned neuroprotection of HPC was attenuated by naltrindole (a selective DOR antagonist). The expression of hypoxia-inducible factor-1α (HIF-1α) and DOR, and the content of leucine enkephalin (L-ENK) in the brain were also investigated after the end of 7-day HPC. HPC upregulated the neuronal expression of HIF-1α and DOR, and synchronously elevated the content of L-ENK in the rat brain. HIF-1α siRNA was used to further elucidate the relationship between HIF-1α and DOR in the HPC-treated brain. Knockdown of HIF-1α by siRNA markedly abrogated the HPC induced upregulation of HIF-1α and DOR. The present study demonstrates that the expression of DOR in the rat brain is upregulated by HIF-1α following exposure to 7-day HPC, at the same time, HPC also increases the production of endogenous DOR ligand L-ENK in the brain. DOR activation after HPC results in prolonged neuroprotection against subsequent global cerebral ischemic injury, suggesting a new mechanism of HPC-induced neuroprotection on global cerebral ischemia following CA and resuscitation.

Topics: Animals; Apoptosis; Arousal; Asphyxia; Behavior, Animal; Blotting, Western; Brain Ischemia; Brain Stem; Enkephalin, Leucine; Fluorescent Antibody Technique; Heart Arrest; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia, Brain; In Situ Nick-End Labeling; Ischemic Preconditioning; Male; Motor Activity; Naltrexone; Narcotic Antagonists; Postural Balance; Rats; Real-Time Polymerase Chain Reaction; Receptors, Opioid, delta; RNA, Small Interfering; Seizures; Survival Analysis

We previously reported that the δ opioid receptor (DOP) agonists SNC80 and TAN-67 produce potent antidepressant-like and antinociceptive effects in rodents. However, SNC80 produced convulsive effects. Recently, we succeeded in synthesizing a novel DOP agonist called KNT-127. The present study examined the convulsive, antidepressant-like, and antinociceptive effects of KNT-127 in mice. In contrast to SNC80, KNT-127 produced no convulsions at doses of up to 100mg/kg. In mice subjected to the forced swim test, a screening model for antidepressants, KNT-127 (1mg/kg, s.c.) significantly decreased the duration of immobility and increased the duration of swimming without influencing spontaneous locomotor activity. These behavioral changes were similar to that observed for the tricyclic antidepressant imipramine (6mg/kg). The antidepressant-like effect of KNT-127 in mice was antagonized by pretreatment with naltrindole (NTI), a selective DOP antagonist, or naltriben, a putative DOP(2) subtype antagonist. In addition, KNT-127 (3mg/kg, s.c.) significantly reduced the number of acetic acid-induced abdominal constrictions and the duration of licking time, respectively, in mice subjected to a writhing test and a formalin test. These antinociceptive effects were antagonized by pretreatment with either NTI or 7-benzylidenenaltrexone, a putative DOP(1) subtype antagonist. We propose that KNT-127 should be considered as a candidate compound for the development of DOP-based antidepressants and/or analgesics that lack convulsive effects.

Topics: Analgesics; Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic; Behavior, Animal; Benzamides; Depression; Dopamine Antagonists; Imipramine; Male; Mice; Mice, Inbred ICR; Morphinans; Motor Activity; Naltrexone; Narcotic Antagonists; Pain Measurement; Piperazines; Receptors, Opioid, delta; Seizures; Swimming

Postictal movement dysfunction is a common symptom in patients with epilepsy. We investigated the involvement of opioid receptors in the nucleus accumbens (NAC) in amygdaloid kindling-induced postictal decrease in locomotion (PDL) in rats. Seizures were induced by daily electrical stimulation of the basolateral amygdala until four consecutive stage 5 seizures were elicited. Locomotion was quantified before and after infusion of an opioid receptor antagonist or saline into the NAC. Whereas PDL was induced after a stage 5 seizure in saline-infused rats, pre-infusion of the mu opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP, 5 microg/1 microL/side) into the NAC prevented PDL. Pre-infusion of delta (naltrindole, 30 microg/1 microL/side), kappa (nor-binaltorphimine, 1.8 microg/1 microL/side), or nonselective (naloxone, 10 microg/1 microL/side) opioid receptor antagonists did not block PDL, but late postictal hyperactivity was blocked by naltrindole. None of the antagonists affected amygdaloid evoked afterdischarge duration. It is suggested that mu opioid receptors in the NAC participate in amygdaloid seizure-induced PDL without affecting seizure duration.

Topics: Amygdala; Animals; Epilepsy; Kindling, Neurologic; Locomotion; Male; Naloxone; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Rats; Rats, Long-Evans; Receptors, Opioid, mu; Seizures

Opioid systems in hippocampus regulate excitability and kappa opioids have a role in anticonvulsant protection, but their mechanisms of action are incompletely understood. We examined the ability of opioid and nonopioid agents with overlapping ionic mechanisms and actions similar to kappa opioid agonists, to block seizures in rat models of encephalitis due to Borna Disease virus and Herpes Simplex Virus Type-1. Naltrindole, a delta antagonist and thus a kappa opioid sparing agent, (10 mg/kg s.c.) blocked spontaneous and naloxone (opioid antagonist)-induced seizures in the models, but produced somatic signs similar to opioid withdrawal. Given that delta antagonists as well as kappa opioid agonists in hippocampus enhance potassium M currents (I(M)), we tested the effect of the I(M) augmenter flupirtine. Flupirtine (20 mg/kg i.p.) prevented seizures in Borna and herpes infected rats, without signs of withdrawal, hypotonia or sedation. The results support the efficacy of opioid and nonopioid drugs in modulating naloxone-induced seizures in critical illness due to viral encephalitis and by analogy, opioid withdrawal seizures.

Topics: Aminopyridines; Analgesics; Animals; Anticonvulsants; Borna Disease; Encephalitis, Viral; Herpes Simplex; Herpesvirus 1, Human; Male; Naloxone; Naltrexone; Narcotic Antagonists; Potassium; Rats; Rats, Inbred Lew; Receptors, Opioid, delta; Seizures; Substance Withdrawal Syndrome

A new method for the preparation of N-benzylpyrrolomorphinans has been developed. Thus Michael reaction of the benzylimines of oxycodones and oxymorphones with nitrostyrenes gave a series of 4'-aryl-N-benzylpyrrolomorphinans. These were selective delta antagonists of much higher in vitro potency (with 5a having K(e) delta = <1 nM) than their binding affinities predicted. In mice in vivo assays 5a showed good delta antagonist activity in the anti-writhing analgesic assay and also inhibited delta agonist-induced convulsant activity.

Topics: Animals; CHO Cells; Cricetinae; Humans; In Vitro Techniques; Ligands; Male; Mice; Morphinans; Narcotic Antagonists; Radioligand Assay; Receptors, Opioid, delta; Seizures; Structure-Activity Relationship; Transfection; Vas Deferens

N-Cyclopropylmethyl-[7alpha,8alpha,2', 3']-cyclohexano-1'[S]-hydroxy-6,14-endo-ethenotetrahydronororip avine (BU48) is a novel, ring-constrained analog of buprenorphine. In vivo, BU48 (0.1-10 mg/kg s.c.) produced brief, nonlethal convulsions in mice followed by brief Straub tail and a short period of catalepsy characteristic of BW373U86 and other nonpeptidic delta-receptor agonists. BU48-induced convulsions were sensitive to antagonism by naltrindole (10 mg/kg s.c.) and were also prevented by administration of the putative delta(1) antagonist 7-benzylidenenaltrexone and the putative delta(2) antagonist naltriben, with the latter being more potent. In the abdominal stretch assay in the mouse, only low-efficacy antinociceptive activity of BU48 (0.1-10 mg/kg) was seen. This was reversed by the kappa-opioid antagonist norbinaltorphimine (32 mg/kg s.c.) but not by the delta-opioid antagonist naltrindole (10 mg/kg s.c.). BU48 (10 mg/kg s.c.) acted as a delta-antagonist in this assay. In mouse brain homogenates, BU48 had high (nanomolar) binding affinity for all three opioid receptors in the order mu > delta = kappa. In vitro, the compound acted as a potent (EC(50) = 1.4 nM) kappa-opioid agonist in the guinea pig ileum and a potent (EC(50) = 0.2 nM) delta-opioid agonist in the mouse vas deferens but showed partial agonist activity at the rat cloned delta-opioid (40%) and human cloned kappa-opioid (59%) receptors with very low efficacy at the rat cloned mu-opioid receptor (10%); findings consistent with its in vivo profile. BU48 is the first described compound that produces delta-opioid-mediated convulsions without any evidence of delta-opioid-mediated antinociception and will be a useful tool in investigations of the delta-opioid receptor.

Topics: Analgesics, Opioid; Animals; Benzamides; Brain; Buprenorphine; Convulsants; Electric Stimulation; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Ileum; In Vitro Techniques; Male; Mice; Muscle Contraction; Muscle, Smooth; Naltrexone; Narcotic Antagonists; Pain Measurement; Piperazines; Radioligand Assay; Rats; Receptors, Opioid, delta; Receptors, Opioid, kappa; Seizures; Vas Deferens

The role of delta-opioid receptors on the development of kindling induced by the convulsant pentylenetetrazol (37.5 mg kg(-1) i.p.) was investigated in rats. Besides the seizure development, the kindling induced enhancement of glutamate binding and the kindling-induced learning deficit were examined. A clear depression of kindling development by blocking of delta-opioid receptors by intracerebroventricular administration of naltrindole (10 nmol/5 microl) was found. In an acute convulsion test performed 8 days after kindling completion, animals pretreated with naltrindole during kindling induction showed lower seizure stages compared to saline-pretreated kindled animals. The kindling-induced increase in hippocampal glutamate binding was completely prevented by naltrindole, whereas the kindling-induced learning deficit was not influenced. The learning performance of control animals pretreated with naltrindole was very low. It was hypothesized that the various consequences of kindling induction could be influenced separately. Summarizing the results, an involvement of the delta-opioid system in mechanisms underlying chemical kindling was clearly demonstrated. Interactions of endogenous opioid systems with glutamatergic transmission were suggested.

Topics: Animals; Convulsants; Drug Interactions; Glutamic Acid; Injections, Intraventricular; Kindling, Neurologic; Learning Disabilities; Male; Naltrexone; Narcotic Antagonists; Pentylenetetrazole; Rats; Rats, Wistar; Receptors, Opioid, delta; Seizures; Time Factors

Endogenous opioids modulate processes of central excitability such as long-term potentiation and electrical kindling. Little is known about the neurochemical alterations in the interaction of the glutamatergic and opioid system in the development of pentylenetetrazol (PTZ) kindling in rats. Therefore, in the present study we investigated glutamate, DAMGO and naltrindole receptor binding, receptor protein expression by Western blot and ex vivo glutamate transmitter release in PTZ kindled rats. The specific 3H-DAMGO and -naltrindole binding to hippocampal membranes displayed no significant changes in kindled rats compared to controls. In contrast, the 3H-l-glutamate binding was significantly enhanced after completion of PTZ kindling. The expression of receptor protein for glutamate as well as the naloxone- and naltrindole-induced 3H-d-aspartate release from hippocampal slices did not alter in any case as a consequence of PTZ kindling. The PTZ induced enhancement of the glutamate binding sites in the hippocampus was downregulated to control level by natrindole treatment of rats prior to each PTZ application. Furthermore, naltrindole pretreatment of rats significantly inhibited the development of seizure susceptibility. In contrast, naloxone was not able to alter the seizure activity induced by PTZ as well as the transmitter receptor binding. The results are discussed in the light of a modulating role of delta-opioid receptors in PTZ kindling.

Topics: Animals; Convulsants; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Hippocampus; In Vitro Techniques; Kindling, Neurologic; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pentylenetetrazole; Rats; Rats, Wistar; Receptors, Glutamate; Receptors, Opioid; Seizures; Synapses

The potentiation of the toxic and lethal effects of cocaine by the selective delta-opioid receptor antagonist naltrindole was explored in unrestrained, unanesthetized rats that received a continuous intravenous infusion of cocaine until death. The lethal dose of cocaine was lowered dose dependently in animals administered naltrindole intracisternally (3.0-30 microg), but not intravenously (30-300 microg). There was also a decrease in the lethal dose of cocaine following an injection of the nonselective opioid antagonist naltrexone, but not naloxone. However, the seizure-producing dose of cocaine was decreased dose dependently in rats that received naltrindole, regardless of the route of administration, naloxone, or naltrexone. In contrast, the effect of cocaine on heart rate was altered only by centrally administered naltrindole or intravenous naltrexone, with a dose of 30 microg naltrindole and 10 mg/kg naltrexone abolishing the bradycardic effect of cocaine. Despite this, neither naltrindole nor naltrexone changed the hypertensive effect of cocaine. Higher doses of naltrindole (100 microg i.c.) produced significant increases in heart rate and mean arterial pressure and were not tested in combination with cocaine. Because the lethal dose of cocaine was reduced only when naltrindole was administered intracisternally, the potentiation of the lethal effects of cocaine by naltrindole is through a central mechanism of action that may involve changes in cardiovascular function.

Topics: Animals; Blood Pressure; Central Nervous System; Cisterna Magna; Cocaine; Drug Synergism; Heart Rate; Infusions, Intravenous; Injections; Male; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Seizures

I.c.v. injection for 9 days of either naltexone (NTX) (5, 10, 20, 40 micrograms/rat) or a selective mu peptide (CTOP) (0.125, 0.25, 0.5, 1, 3, 6 micrograms/rat) or delta (naltrindole) (NLT) (5, 10, 20 micrograms/rat) subtype opioid receptor antagonist affected sensitization to cocaine (COC) (50 mg/kg, i.p.) administered 10 min after. NTX (5 and 40 micrograms/rat), NLT (10 and 20 micrograms/rat), and the peptide CTOP (0.25-0.5 microgram/rat) attenuated seizure parameters (percent of animals showing seizures, mean score and latency) in a day-related manner. The DD50 (days to reach 50% of death) value for COC was 2.69, whereas it was 9.67 and 7.27 for NTX 5 and 40 micrograms/rat, 8.59 for NLT (10 micrograms/rat), and 6.11, 5.95, and 4.30 for CTOP (0.25, 0.5, and 1 microgram/rat respectively). These findings suggest a concurrent involvement of mu- and delta-opioid receptor subtype in COC-induced sensitization to toxic effects.

Topics: Animals; Cocaine-Related Disorders; Male; Naltrexone; Narcotic Antagonists; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu; Seizures; Somatostatin