Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, School of Medicine of Ribeirão Preto of the University of São Paulo (USP), Av. dos Bandeirantes, 3900, Ribeirão Preto (SP), 14049-900, Brazil; Institute for Neuroscience and Behavior (INeC), Av. do Café, S/N, Ribeirão Preto (SP), Brazil.
Synapse. 2014 Jan;68(1):16-30. doi: 10.1002/syn.21697. Epub 2013 Oct 22.
The periaqueductal gray matter (PAG) consists in a brainstem structure rich in 5-hydroxytryptamine (5-HT) inputs related to the modulation of pain. The involvement of each of the serotonergic receptor subtypes found in PAG columns, such as the dorsomedial (dmPAG) and the ventrolateral (vlPAG) columns, regarding post-ictal antinociception have not been elucidated. The present work investigated the participation of the dmPAG and vlPAG columns in seizure-induced antinociception. Specifically, we studied the involvement of serotonergic neurotransmission in these columns on antinociceptive responses that follow tonic-clonic epileptic reactions induced by pentylenetetrazole (PTZ), an ionophore GABA-mediated Cl(-) influx antagonist. Microinjections of cobalt chloride (1.0 mM CoCl2 /0.2 µL) into the dmPAG and vlPAG caused an intermittent local synaptic inhibition and decreased post-ictal antinociception that had been recorded at various time points after seizures. Pretreatments of the dmPAG or the vlPAG columns with the nonselective serotonergic receptors antagonist methysergide (5.0 µg/0.2 µL) or intramesencephalic microinjections of ketanserin (5.0 µg/0.2 µL), a serotonergic antagonist with more affinity to 5-HT2A/2C receptors, decreased tonic-clonic seizure-induced antinociception. Both dmPAG and vlPAG treatment with either the 5-HT2A receptor selective antagonist R-96544 (10 nM/0.2 µL), or the 5-HT2C receptors selective antagonist RS-102221 (0.15 µg/0.2 µL) also decrease post-ictal antinociception. These findings suggest that serotonergic neurotransmission, which recruits both 5-HT2A and 5-HT2C serotonergic receptors in dmPAG and vlPAG columns, plays a critical role in the elaboration of post-ictal antinociception.
导水管周围灰质（PAG）是脑干部位富含 5-羟色胺（5-HT）输入的结构，与疼痛调节有关。PAG 柱中发现的每种 5-羟色胺能受体亚型（如背内侧（dmPAG）和腹外侧（vlPAG）柱）在发作后镇痛中的作用尚未阐明。本研究探讨了 dmPAG 和 vlPAG 柱在癫痫发作引起的镇痛中的作用。具体而言，我们研究了 5-羟色胺能神经传递在这些柱中的参与对戊四氮（PTZ）诱导的强直-阵挛性癫痫反应后镇痛反应的影响，PTZ 是一种离子载体 GABA 介导的 Cl(-)内流拮抗剂。将氯化钴（1.0 mM CoCl2/0.2 µL）微注射到 dmPAG 和 vlPAG 中会导致间歇性局部突触抑制，并降低在癫痫发作后不同时间点记录的发作后镇痛。dmPAG 或 vlPAG 柱的预处理，用非选择性 5-羟色胺能受体拮抗剂麦角乙脲（5.0 µg/0.2 µL）或内侧脑室内微注射酮色林（5.0 µg/0.2 µL），一种对 5-HT2A/2C 受体亲和力更高的 5-羟色胺能拮抗剂，降低强直-阵挛性癫痫发作引起的镇痛。dmPAG 和 vlPAG 用 5-HT2A 受体选择性拮抗剂 R-96544（10 nM/0.2 µL）或 5-HT2C 受体选择性拮抗剂 RS-102221（0.15 µg/0.2 µL）处理，也会降低发作后镇痛。这些发现表明，5-羟色胺能神经传递，它在 dmPAG 和 vlPAG 柱中募集 5-HT2A 和 5-HT2C 5-羟色胺能受体，在发作后镇痛的产生中起着关键作用。
