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Nociceptin, OP4 receptor ligand in different models of experimental epilepsy
Andrzej Rubaj1, Witold Zgodzinski, Katarzyna Gustaw
1Department of Cardiology, Medical University of Lublin, Jaczewskiego 8, 20-090, Lublin, Poland.
Abstract:
The anticonvulsive activity of nociceptin, endogenous OP4 receptors agonist was investigated in pentylenetetrazole (PTZ), N-methyl D-aspartic acid (NMDA), bicucculine (BCC) and electrically evoked seizure models of experimental epilepsy. Nociceptin, at the dose of 10 nmol, suppressed the clonic seizures induced by PTZ, NMDA and BCC. [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 which has been proposed to be selective antagonist OP4 receptors, did not prevent the action of nociceptin. The effect of [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 on seizures induced by PTZ, NMDA and BCC was very similar to that of nociceptin. These data support the hypothesis that it possesses agonistic properties. Naloxone did not reverse the anticonvulsive action of nociceptin as well as [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 which excludes the participation of opioid receptor in this action. On the other hand in the electroconvulsive model of generalized seizures, nociceptin as well as [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 influenced neither the electroconvulsive threshold nor the maximal electroshock test. The data suggest that nociceptin and [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 can exert anticonvulsive action. These properties depend on OP4 but not opioid receptors activation.
Insights
Nociceptin, an endogenous agonist for OP4 receptors, demonstrated anticonvulsive activity in various epilepsy models. Its effects were mediated by OP4 receptor activation, not opioid receptors, suggesting a potential therapeutic role.
Area of Science:
- Neuroscience
- Pharmacology
- Epilepsy Research
Background:
- Epilepsy is a neurological disorder characterized by recurrent seizures.
- Nociceptin is an endogenous peptide and agonist of the opioid receptor-like 1 (ORL1) or nociceptin/orphanin FQ peptide (NOP) receptor, also known as OP4.
- The anticonvulsive properties of nociceptin and its potential mechanisms of action are not fully understood.
Purpose of the Study:
- To investigate the anticonvulsive activity of nociceptin in various experimental epilepsy models.
- To determine the involvement of OP4 receptors and opioid receptors in the anticonvulsive effects of nociceptin.
- To evaluate the potential of nociceptin as a therapeutic agent for epilepsy.
Main Methods:
- Administration of nociceptin and a proposed OP4 receptor antagonist ([Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2) in pentylenetetrazole (PTZ), N-methyl D-aspartic acid (NMDA), and bicuculline (BCC) induced seizure models.
- Assessment of anticonvulsive effects by observing seizure suppression.
- Evaluation of the involvement of opioid receptors using naloxone.
- Testing in electroconvulsive threshold and maximal electroshock tests to assess effects on generalized seizures.
Main Results:
- Nociceptin (10 nmol) effectively suppressed clonic seizures induced by PTZ, NMDA, and BCC.
- The proposed OP4 receptor antagonist ([Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2) exhibited similar anticonvulsive effects to nociceptin, supporting its agonistic properties.
- Naloxone did not reverse the anticonvulsive actions, indicating no involvement of opioid receptors.
- Neither nociceptin nor the antagonist affected the electroconvulsive threshold or maximal electroshock test, suggesting specific activity against certain seizure types.
Conclusions:
- Nociceptin exhibits significant anticonvulsive properties in chemical and electrical seizure models.
- The anticonvulsive effects of nociceptin are mediated through the activation of OP4 receptors.
- Opioid receptors do not play a role in the anticonvulsive action of nociceptin.
- Nociceptin and its analogs show promise as potential therapeutic agents for specific epilepsy types.