title: Intrinsic neural circuits between dorsal midbrain neurons that control fear-induced responses and seizure activity and nuclei of the pain inhibitory system elaborating postictal antinociceptive processes: a functional neuroanatomical and neuropharmacological study.
abstract: The blockade of GABA-mediated Cl(-) influx with pentylenetetrazol (PTZ) was used in the present work to induce seizures in Rattus norvegicus. The aim of this work was to study the involvement of monoamines in the antinociception induced by convulsions elicited by peripheral administration of PTZ (64 mg/kg). The analgesia was measured by the tail-flick test in seven or eight Wistar rats per group. Convulsions were followed by statistically significant increase in the tail-flick latencies (TFL), at least for 120 min of the postictal period. Peripheral administration of methysergide (0.5, 1, 2, and 3 mg/kg) caused a significant decrease in the TFL in seizing animals, as compared to controls, in all postictal periods studied. These findings were corroborated by the pretreatment with ketanserin, a 5-HT(2A/2C)-serotonergic/alpha(1)-noradrenergic receptors antagonist, at the same doses. Peripheral administration of yohimbine (0.5, 1, 2, and 3 mg/kg), alpha(2)-noradrenergic antagonist, also decreased the postictal analgesia either at initial or more terminal periods of the postictal analgesia. These data were corroborated with peripheral administrations of propranolol, a beta-noradrenergic receptor blocker that caused a decrease in the postictal analgesia consistently in later stages (after the first 20-min post-tonic-clonic convulsive reactions) of the post-seizure analgesia, except for the highest dose. These results indicate that monoamines may be involved in the postictal analgesia. The blockade of 5-HT(2A/2C)-serotoninergic, alpha(1)-noradrenergic, or alpha(2)-noradrenergic receptors before tonic clonic seizure-induced analgesia antagonized the increase in the nociceptive threshold caused by seizures in initial steps of the temporal antinociceptive curve, as compared to the blockade of beta-noradrenergic ones. These findings suggest that the recruitment of alpha-noradrenergic receptor and serotonergic receptors was made immediately after convulsions and in other initial periods of the postictal analgesia, as compared to the involvement of beta-noradrenergic receptor. Neurochemical lesions of the locus coeruleus (LC) and neuronal damage of the dorsal raphe nucleus induced a significant decrease of the postictal analgesia, suggesting the involvement of these nuclei in this antinociceptive process. The functional neuroanatomical study of the neural link between the mesencephalic tectum and nuclei of the central pain inhibitory system showed evidence for the interconnection between superior colliculus, both dorsal and ventral periaqueductal gray matter (PAG), and inferior colliculus. Defensive substrates of the inferior colliculus, also involved with wild running and epilepsy, send inputs toward dorsal raphe nucleus and locus coeruleus. Since these nuclei are rich in monoamines and send neural connections toward other monoaminergic nuclei of the brainstem involved with the control of the nociceptive inputs in the dorsal horn of the spinal cord, the present results offer a neuroanatomical and psychopharmacological basis for the antinociceptive processes following tonic-clonic seizures.
authors.affiliation: Laboratório de Neuroanatomia e Neuropsicobiologia, Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, 14049-900 Avenida dos Bandeirantes, 3900 Ribeirão Preto (SP), Brasil.
authors.forename: Renato L
authors.initials: RL
authors.lastname: Freitas
authors.forename: Célio M R
authors.initials: CM
authors.lastname: Ferreira
authors.forename: Sandro J
authors.initials: SJ
authors.lastname: Ribeiro
authors.forename: Andressa D
authors.initials: AD
authors.lastname: Carvalho
authors.forename: Daoud H
authors.initials: DH
authors.lastname: Elias-Filho
authors.forename: Norberto
authors.initials: N
authors.lastname: Garcia-Cairasco
authors.forename: Norberto Cysne
authors.initials: NC
authors.lastname: Coimbra
mesh_terms: D018674:Adrenergic Antagonists / Q000494:pharmacology; D000818:Animals; D015306:Biogenic Monoamines / Q000502:physiology; D005239:Fear / Q000502:physiology*; D007245:Inferior Colliculi / Q000166:cytology / Q000502:physiology; D008125:Locus Coeruleus / Q000502:physiology; D008297:Male; D008636:Mesencephalon / Q000166:cytology* / Q000187:drug effects / Q000503:physiopathology; D008845:Microinjections; D009433:Neural Inhibition / Q000502:physiology*; D009434:Neural Pathways / Q000166:cytology* / Q000187:drug effects / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects; D010433:Pentylenetetrazole; D010487:Periaqueductal Gray / Q000166:cytology / Q000502:physiology; D011903:Raphe Nuclei / Q000502:physiology; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013477:Superior Colliculi / Q000166:cytology / Q000502:physiology
chemical_list: D018674:Adrenergic Antagonists; D015306:Biogenic Monoamines; D012702:Serotonin Antagonists; D010433:Pentylenetetrazole