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Studies on the anticonvulsant effect of U50488H on maximal electroshock seizure in mice
Anshu Manocha1, Pramod Kumari Mediratta, Krishna Kishore Sharma
1Department of Pharmacology, University College of Medical Sciences & GTB Hospital, Shahdara, 110095, Delhi, India. anshumanocha@hotmail.com
Abstract:
The present study was designed to investigate the effect of U50488H, a prototype non-peptide kappa opioid agonist on convulsive behaviour using a maximal electroshock (MES) seizure test in mice. An attempt was also made to explore the role of possible receptors involved. MES seizures were induced via transauricular electrodes (60 mA, 0.2 s). Seizure severity was evaluated by means of two parameters, i.e., (1). duration of tonic hindlimb extensor phase and (2). mortality due to convulsions. Intraperitoneal (i.p.) administration of U50488H dose dependently (5-20 mg/kg) decreased the hindlimb extensor phase of MES. The anticonvulsant effect of U50488H was attenuated by the general opioid antagonist, naloxone at a high dose, and by MR2266, a selective kappa antagonist, but not by naltrindole, a delta antagonist. Coadministration of gamma-aminobutyric acid (GABA)ergic drugs (diazepam, GABA, muscimol, and baclofen) and the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK801), with U50488H augmented the anticonvulsant effect of the latter drug in mice. On the other hand, flumazenil, a central benzodiazepine (BZD) receptor antagonist, reversed the protective effect of diazepam and similarly, delta-aminovaleric acid (DAVA), a GABA(B) receptor antagonist, blocked the protective effect of baclofen, a GABA(B) agonist on the anti-MES action of U50488H. These BZD-GABAergic antagonists, namely, flumazenil or DAVA, on their own also counteracted the anti-electroshock seizure effect of U50488H given alone. However, mortality was not significantly altered in any of the above animal groups. Taken together, the findings have shown a possible role for multitude of important neurotransmitter systems, i.e., opioid (kappa), NMDA channel, GABA(A)-BZD-chloride channel complex, and GABA(B) receptors in the anticonvulsant action of U50488H.
Insights
U50488H, a kappa opioid agonist, demonstrated anticonvulsant effects in mice by reducing seizure duration. Its action involves kappa opioid receptors and interacts with GABAergic and NMDA systems, suggesting a complex role in seizure control.
Area of Science:
- Neuroscience
- Pharmacology
- Convulsive behavior research
Background:
- Opioid receptors, particularly kappa opioid receptors, play a role in modulating neuronal excitability.
- Understanding the neurochemical basis of anticonvulsant activity is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To investigate the anticonvulsant effects of U50488H, a kappa opioid agonist, in a mouse maximal electroshock (MES) seizure model.
- To explore the involvement of various neurotransmitter systems, including opioid, GABAergic, and NMDA receptors, in the anticonvulsant action of U50488H.
Main Methods:
- Maximal electroshock (MES) seizures were induced in mice using transauricular electrodes.
- U50488H was administered intraperitoneally at doses of 5-20 mg/kg.
- Anticonvulsant effects were assessed by measuring the duration of the tonic hindlimb extensor phase and mortality.
- Interactions with opioid antagonists (naloxone, MR2266, naltrindole), GABAergic drugs, and NMDA receptor antagonists were evaluated.
Main Results:
- U50488H dose-dependently reduced the duration of the tonic hindlimb extensor phase in MES-induced seizures.
- The anticonvulsant effect of U50488H was blocked by kappa-selective antagonist MR2266 and high-dose naloxone, but not by delta antagonist naltrindole.
- Coadministration with GABAergic agents (diazepam, GABA, muscimol, baclofen) and NMDA antagonist dizocilpine (MK801) enhanced U50488H's anticonvulsant effect.
- Benzodiazepine receptor antagonist flumazenil and GABA(B) receptor antagonist DAVA reversed the effects of diazepam and baclofen, respectively, and also counteracted U50488H's anticonvulsant action when administered alone.
Conclusions:
- U50488H exhibits significant anticonvulsant properties in the MES model.
- The findings suggest that the anticonvulsant action of U50488H involves kappa opioid receptors.
- Neurotransmitter systems including GABA(A)-benzodiazepine-chloride channel complex, GABA(B) receptors, and NMDA receptors modulate the anticonvulsant effects of U50488H.
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