Laboratório de Neuroanatomia & Neuropsicobiologia, Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FMRP-USP), Av. dos Bandeirantes 3900, Ribeirão Preto, SP 14049-900, Brazil.
Neuropharmacology. 2013 Apr;67:379-94. doi: 10.1016/j.neuropharm.2012.10.024. Epub 2012 Nov 29.
Decrease of γ-aminobutyric acid (GABA)-mediated neurotransmission in the dorsomedial hypothalamus (DMH) evokes instinctive fear-like responses. The aim of the present study was to investigate the involvement of the serotonin (5-HT)- and norepinephrine-mediated pathways of the endogenous pain inhibitory system, including the dorsal raphe nucleus (DRN) and the locus coeruleus (LC), in the defensive responses and antinociceptive processes triggered by the blockade of GABAergic receptors in the DMH. The intra-hypothalamic microinjection of the GABA(A) receptor antagonist bicuculline (40 ng/200 nL) elicited elaborate defensive behaviours interspersed with exploratory responses. This escape behaviour was followed by significantly increased pain thresholds, a phenomenon known as fear-induced antinociception. Furthermore, at 5 and 14 days after DRN serotonin-containing neurons were damaged using the selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), the frequency and duration of alertness and escape behaviour evoked by the GABA(A) receptor blockade in the DMH decreased, as well as fear-induced antinociception. Pre-treatment with the non-selective 5-HT receptor antagonist methysergide, the 5-HT(2A/2C) receptor antagonist ketanserin and the 5-HT(2A) receptor selective antagonist R-96544 in the LC also decreased fear-induced antinociception, without significant changes in the expression of defensive behaviours. These data suggest that the serotonergic neurons of the DRN are directly involved in the organisation of defensive responses as well as in the elaboration of the innate fear-induced antinociception. However, serotonin-mediated inputs from the NDR to the LC modulate only fear-induced antinociception and not the defensive behaviours evoked by GABA(A) receptor blockade in the DMH.
在背内侧下丘脑（DMH）中 γ-氨基丁酸（GABA）介导的神经传递减少会引起本能的恐惧样反应。本研究的目的是研究内源性疼痛抑制系统的 5-羟色胺（5-HT）和去甲肾上腺素介导途径的参与，包括中缝背核（DRN）和蓝斑（LC），在 GABA 能受体在 DMH 中的阻断引发的防御反应和镇痛过程中。下丘脑内微量注射 GABA(A) 受体拮抗剂荷包牡丹碱（40ng/200nL）引起精心设计的防御行为，穿插着探索反应。这种逃避行为之后是疼痛阈值显著增加，这种现象称为恐惧诱导的镇痛。此外，在使用选择性神经毒素 5,7-二羟基色胺（5,7-DHT）破坏 DRN 中 5-HT 含量神经元 5 天和 14 天后，由 DMH 中 GABA(A) 受体阻断引起的警觉和逃避行为的频率和持续时间减少，以及恐惧诱导的镇痛。LC 中的非选择性 5-HT 受体拮抗剂麦角乙脲、5-HT(2A/2C) 受体拮抗剂酮色林和 5-HT(2A) 受体选择性拮抗剂 R-96544 的预处理也降低了恐惧诱导的镇痛，而防御行为的表达没有显著变化。这些数据表明，DRN 的 5-HT 神经元直接参与防御反应的组织以及先天恐惧诱导的镇痛的精心制作。然而，来自 NDR 的 5-HT 介导的输入到 LC 仅调节恐惧诱导的镇痛，而不调节 GABA(A) 受体在 DMH 中的阻断引起的防御行为。
