The μ1-opioid receptor and 5-HT2A- and 5HT2C-serotonergic receptors of the locus coeruleus are critical in elaborating hypoalgesia induced by tonic and tonic-clonic seizures.
It has been proposed that the post-ictal state is associated with the expression of hypoalgesia. It is clear that the projections among the periaqueductal gray matter (PAG), dorsal raphe nucleus (DRN) and locus coeruleus (LC) play a role in pain management. These mesencephalic structures have direct reciprocal opioid and monoaminergic projections to the LC that can possibly modulate post-ictal hypoalgesia. The goal of this study was to examine if LC-opioid and serotonergic/noradrenergic mechanisms signal the post-ictal hypoalgesic responses to tonic-clonic seizures produced by intraperitoneal administration of pentylenetetrazole (PTZ at 64mg/kg), causing an ionophore γ-aminobutyric acid (GABA)-mediated Cl-influx antagonism. The rodents' nociceptive threshold was measured by the tail-flick test. Intra-LC cobalt chloride (1.0nM/0.2μL) microinjections produced intermittent local synaptic inhibition and were able to reduce post-ictal hypoalgesia. Central administration of naltrexone (a non-selective antagonist for opioid receptors), naloxonazine (a selective antagonist for μ1-opioid-receptors), methysergide (a non-selective antagonist for serotonergic receptors) or ketanserin (an antagonist for both α1-noradrenergic and 5-Hydroxytryptamine(HT)2A/2Creceptors) at 5.0μg/0.2μL, R-96544 (a 5-HT2Areceptor selective antagonist) at 10nM/0.2μL, or RS-102221 (a 5-HT2Creceptor selective antagonist) at 0.15μg/0.2μL into the LC also decreased post-ictal hypoalgesia. The data presented here suggest that the post-ictal antinociception mechanism involves the μ1-opiod, 5-HT2A- and 5-HT2C-serotonergic, and α1-noradrenergic receptors in the LC.
Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, 14049-900 São Paulo, Brazil; Multiuser Centre of Neuroelectrophysiology, Department of Anatomy and Surgery, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, 14049-900 São Paulo, Brazil; Laboratory of Pain and Emotions, Department of Anatomy and Surgery, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, 14049-900 São Paulo, Brazil; Behavioural Neurosciences Institute (INeC), Avenida do Café, 2450, Ribeirão Preto, 14220-030 São Paulo, Brazil.
Renato Leonardo
RL
de Freitas
Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, 14049-900 São Paulo, Brazil; Behavioural Neurosciences Institute (INeC), Avenida do Café, 2450, Ribeirão Preto, 14220-030 São Paulo, Brazil.
Priscila
P
Medeiros
Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, 14049-900 São Paulo, Brazil.
Juliana Almeida
JA
da Silva
Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, 14049-900 São Paulo, Brazil; Behavioural Neurosciences Institute (INeC), Avenida do Café, 2450, Ribeirão Preto, 14220-030 São Paulo, Brazil.
Rithiele Cristina
RC
de Oliveira
Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, 14049-900 São Paulo, Brazil; Behavioural Neurosciences Institute (INeC), Avenida do Café, 2450, Ribeirão Preto, 14220-030 São Paulo, Brazil; Mato Grosso Federal University Medical School (UFMT), Av Alexandre Ferronato, 1200, Reserva 35, Setor Industrial, 78550-000 Sinop, Mato Grosso, Brazil.
Ricardo
R
de Oliveira
Department of Zoology, Islamia College Peshawar, Jamrud Road, University Campus Peshawar, Peshawar 25120, Khyber Pakhtunkhwa, Pakistan.
Farhad
F
Ullah
Department of Eastern Medicine and Surgery, School of Medical and Health Sciences of the University of Poonch Rawalakot, Azad Jammu and Kashmir, Pakistan.
Asmat Ullah
AU
Khan
Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, 14049-900 São Paulo, Brazil; Multiuser Centre of Neuroelectrophysiology, Department of Anatomy and Surgery, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, 14049-900 São Paulo, Brazil; Laboratory of Pain and Emotions, Department of Anatomy and Surgery, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, 14049-900 São Paulo, Brazil; Behavioural Neurosciences Institute (INeC), Avenida do Café, 2450, Ribeirão Preto, 14220-030 São Paulo, Brazil. Electronic address: nccoimbr@fmrp.usp.br.
Norberto Cysne
NC
Coimbra
D000818:Animals; D008125:Locus Coeruleus / Q000503:physiopathology*; D008297:Male; D017288:Pain Threshold / Q000502:physiology; D010433:Pentylenetetrazole / Q000494:pharmacology; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*
D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017450:Receptors, Opioid, mu; D010433:Pentylenetetrazole
5-HT(2A)- and 5-HT(2C)-serotonergic receptors; GABA-A receptor; locus coeruleus; post-ictal antinociception; α(1)-noradrenergic receptors; μ(1)-opiod receptors