5-HT1A/1B, 5-HT6, and 5-HT7 serotonergic receptors recruitment in tonic-clonic seizure-induced antinociception: role of dorsal raphe nucleus.
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-HT(1A/1B), 5-HT(6), and 5-HT(7) 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 microg/0.2 microL) 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-HT(1A) serotonergic autoreceptors in the pain endogenous inhibitory system) and an inhibitory effect (possibly due to a DRN post-synaptic 5-HT(1B), 5-HT(6), and 5-HT(7) 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.
Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Laboratório de Neuroanatomia & Neuropsicobiologia, Ribeirão Preto, SP, Brazil.
Renato Leonardo
RL
Freitas
Célio Marcos dos Reis
CM
Ferreira
Maria Angélica Castiblanco
MA
Urbina
Andrés Uribe
AU
Mariño
Andressa Daiane
AD
Carvalho
Giuseppe
G
Butera
Ana Maria
AM
de Oliveira
Norberto Cysne
NC
Coimbra
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000008:administration & dosage; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D008845:Microinjections / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D010433:Pentylenetetrazole / Q000008:administration & dosage; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D011985:Receptors, Serotonin / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013997:Time Factors
D018756:GABA Antagonists; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D008719:Methiothepin; D010433:Pentylenetetrazole