Journal
EXPERIMENTAL NEUROLOGY
Volume 217, Issue 1, Pages 16-24Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2009.01.003
Keywords
GABA-A receptor; Pentylenetetrazole-induced tonic-clonic seizures; Antinociception; 5-hydroxytryptamine; 5-HT1A/1B receptors; 5-HT6 receptors; 5-HT7 receptors; Dorsal raphe nucleus; Pain; Epilepsy
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Funding
- FAPESP [1996/08574-9, 2002/01496-5, 2007/01174-1, 03/05256-1, 02/01497-1]
- FAEPA [537/1995, 70/2002]
- CNPq [304421/2007-3, 200629/2005-0]
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Pharmacological studies have been focused on the involvement of different neural pathways in the organization of antinociception that follows tonic-clonic seizures, including 5-hydroxytryptamine (5-HT)-, norepinephrine-, acetylcholine- and endogenous opioid peptide-mediated mechanisms, giving rise to more in-depth comprehension of this interesting post-ictal antinociceptive phenomenon. The present work investigated the involvement of 5-HT1A/1B, 5-HT6, and 5-HT7 serotonergic receptors through peripheral pretreatment with methiothepin at doses of 0.5, 1.0, 2.0 and 3.0 mg/kg in the organization of the post-ictal antinociception elicited by pharmacologically (with pentylenetetrazole at 64 mg/kg)-induced tonic-clonic seizures. Methiothepin at 1.0 mg/kg blocked the post-ictal antinociception recorded after the end of seizures, whereas doses of 2.0 and 3.0 mg/kg potentiated the post-ictal antinociception. The nociceptive thresholds were kept higher than those of the control group. However, when the same 5-hydroxytryptamine receptors antagonist was microinjected (at 1.0, 3.0 and 5.0 mu g/0.2 mu L) in the dorsal raphe nucleus, a mesencephalic structure rich in serotonergic neurons and 5-HT receptors, the post-ictal hypo-analgesia was consistently antagonized. The present findings suggest a dual effect of methiothepin, characterized by a disinhibitory effect on the post-ictal antinociception when peripherally administered (possibly due to an antagonism of pre-synaptic 5-HT1A serotonergic autoreceptors in the pain endogenous inhibitory system) and an inhibitory effect (possibly due to a DRN post-synaptic 5-HT1B, 5-HT6, and 5-HT7 serotonergic receptors blockade) when centrally administered. The present data also Suggest that serotonin-mediated mechanisms of the dorsal raphe nucleus exert a key-role in the modulation of the post-ictal antinociception. (C) 2009 Elsevier Inc. All rights reserved.
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