Brain Advance Access originally published online on March 8, 2007
Brain 2007 130(4):1017-1028; doi:10.1093/brain/awl384
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Endogenous dynorphin in epileptogenesis and epilepsy: anticonvulsant net effect via kappa opioid receptors
1Department of Pharmacology, Innsbruck Medical University, Innsbruck, Austria, 2Neurobiology Program, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, Australia
Correspondence to: Dr Christoph Schwarzer, Department of Pharmacology, Innsbruck Medical University, Peter-Mayr-Str. 1a, A-6020 Innsbruck, Austria E-mail: schwarzer.christoph{at}i-med.ac.at
Neuropsychiatric disorders are one of the main challenges of human medicine with epilepsy being one of the most common serious disorders of the brain. Increasing evidence suggest neuropeptides, particularly the opioids, play an important role in epilepsy. However, little is known about the mechanisms of the endogenous opioid system in epileptogenesis and epilepsy. Therefore, we investigated the role of endogenous prodynorphin-derived peptides in epileptogenesis, acute seizure behaviour and epilepsy in prodynorphin-deficient mice.
Compared with wild-type littermates, prodynorphin knockout mice displayed a significantly reduced seizure threshold as assessed by tail-vein infusion of the GABAA antagonist pentylenetetrazole. This phenotype could be entirely rescued by the kappa receptor-specific agonist U-50488, but not by the mu receptor-specific agonist DAMGO. The delta-specific agonist SNC80 decreased seizure threshold in both genotypes, wild-type and knockout. Pre-treatment with the kappa selective antagonist GNTI completely blocked the rescue effect of U-50488.
Consistent with the reduced seizure threshold, prodynorphin knockout mice showed faster seizure onset and a prolonged time of seizure activity after intracisternal injection of kainic acid. Three weeks after local injection of kainic acid into the stratum radiatum CA1 of the dorsal hippocampus, prodynorphin knockout mice displayed an increased extent of granule cell layer dispersion and neuronal loss along the rostrocaudal axis of the ipsi- and partially also of the contralateral hippocampus. In the classical pentylenetetrazole kindling model, dynorphin-deficient mice showed significantly faster kindling progression with six out of eight animals displaying clonic seizures, while none of the nine wild-types exceeded rating 3 (forelimb clonus). Taken together, our data strongly support a critical role for dynorphin in the regulation of hippocampal excitability, indicating an anticonvulsant role of kappa opioid receptors, thereby providing a potential target for antiepileptic drugs.
Key Words: temporal lobe epilepsy; opioid system; hippocampus; seizure threshold; excitatory neurotransmission
Abbreviations: DOR, delta opioid receptors; GABA, gamma aminobutyric acid; GCL, granule cell layer; KA, kainic acid; KOR, kappa opioid receptors; MOR, mu opioid receptors; NMDA, N-methyl-D-aspartate; mTLE, mesial temporal lobe epilepsy; TRE, transactivator responsive element
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Received July 17, 2006. Revised October 31, 2006. Accepted December 18, 2006.
*Present address: Department of Physiology and Pharmacology, Pasteur Institute of Iran, Pasteur avenue, Tehran, Iran
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