Centre for Comparative and Clinical Anatomy, University of Bristol, Bristol, UK.
J Neuroendocrinol. 2012 Dec;24(12):1527-41. doi: 10.1111/j.1365-2826.2012.02361.x.
Central nociceptin/orphanin FQ (N/OFQ)-expressing neurones are abundantly expressed in the hypothalamus and limbic system and are implicated in the regulation of activity of the hypothalamic-pituitary-adrenal axis (HPA) and stress responses. We investigated the role of the endogenous N/OFQ receptor (NOP) system using the nonpeptidic NOP antagonist, JTC-801 [N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxy-methyl)benzamide monohydrochloride], during the HPA axis response to acute physical/psychological stress (60 min of restraint). Although i.v. JTC-801 (0.05 mg/kg in 100 μl) had no significant effect on restraint-induced plasma corticosterone release at 30 or 60 min post-injection, i.v. JTC-801 (0.05 mg/kg in 100 μl) in quiescent rats significantly increased basal plasma corticosterone at the 30-min time-point compared to i.v. vehicle (1% dimethysulphoxide in sterile saline). Central injection of JTC-801 i.c.v. was associated with increased Fos expression in the parvocellular paraventricular nucleus 90 min after infusion compared to vehicle control. These findings contrast to the effects of i.c.v. UFP-101, a NOP antagonist that we have previously shown to have no effect on HPA activity in quiescent rats. To determine whether restraint stress was associated with compensatory changes in N/OFQ precursor (ppN/OFQ) or NOP receptor mRNAs, in a separate study, we undertook reverse transcriptase-polymerase chain reaction and in situ hybridisation analysis of ppN/OFQ and NOP transcripts in the brains of male Sprague-Dawley rats. In support of an endogenous role for central N/OFQ in psychological stress, we found that acute restraint significantly decreased preproN/OFQ transcript expression in the hippocampus 2 h after stress compared to unstressed controls. PpN/OFQ mRNA was also reduced in the mediodorsal forebrain 4 h after stress. NOP mRNA was reduced in the hypothalamus 2 h after restraint and at 4 h in mediodorsal forebrain and hippocampus. In situ hybridisation analysis showed that acute restraint significantly decreased ppNN/OFQ in the central amygdala, with significantly increased expression in bed nucleus and reticular thalamus associated with repeated restraint. There was a strong trend for reduced NOP mRNA in the bed nucleus of acute and repeated restraint groups, although there were no other significant changes seen. Although the exact mechanisms require elucidation, the findings obtained in the present study provide evidence indicating that the endogenous N/OFQ system is involved in both acute and chronic restraint stress responses. In summary, our findings confirm the significant role of endogenous NOP receptors and tonic N/OFQ function in the response to the psychological stress of restraint.
中央孤啡肽/孤啡肽 FQ（N/OFQ）表达神经元在下丘脑和边缘系统中大量表达，并参与调节下丘脑-垂体-肾上腺轴（HPA）和应激反应的活动。我们使用非肽 N/OFQ 受体（NOP）拮抗剂 JTC-801 [N-（4-氨基-2-甲基喹啉-6-基）-2-（4-乙基苯氧基甲基）苯甲酰胺单盐酸盐]研究了内源性 N/OFQ 受体（NOP）系统在急性生理/心理应激（60 分钟束缚）期间对 HPA 轴反应的作用。尽管静脉内 JTC-801（0.05mg/kg 在 100μl 中）在注射后 30 或 60 分钟时对束缚诱导的血浆皮质酮释放没有显著影响，但在安静的大鼠中，静脉内 JTC-801（0.05mg/kg 在 100μl 中）在 30 分钟时间点显着增加了基础血浆皮质酮水平，与静脉内载体（1%二甲亚砜在无菌盐水中）相比。与载体对照相比，中央注射 JTC-801 脑室（i.c.v.）与输注后 90 分钟时旁室核中小细胞区的 Fos 表达增加有关。这些发现与我们之前表明的中央注射 UFP-101（一种 NOP 拮抗剂）对安静大鼠的 HPA 活性没有影响的作用形成对比。为了确定束缚应激是否与 N/OFQ 前体（ppN/OFQ）或 NOP 受体 mRNA 的代偿性变化有关，在另一项研究中，我们对雄性 Sprague-Dawley 大鼠的大脑进行了 ppN/OFQ 和 NOP 转录物的逆转录-聚合酶链反应和原位杂交分析。为了支持中央 N/OFQ 在心理应激中的内源性作用，我们发现急性束缚在应激后 2 小时显着降低了海马体中的 preproN/OFQ 转录物表达，与未应激对照相比。应激后 4 小时，ppN/OFQ mRNA 也减少了中脑腹侧前脑。应激后 2 小时下丘脑和 4 小时中脑腹侧前脑和海马体中 NOP mRNA 减少。原位杂交分析显示，急性束缚显着减少了中央杏仁核中的 ppN/OFQ，与反复束缚相关的核床和网状丘脑中的表达显着增加。尽管没有其他明显变化，但急性和反复束缚组中 NOP mRNA 的趋势明显减少。尽管确切的机制需要阐明，但本研究的结果提供了证据表明，内源性 N/OFQ 系统参与了急性和慢性束缚应激反应。总之，我们的发现证实了内源性 NOP 受体和紧张 N/OFQ 功能在束缚引起的心理应激反应中的重要作用。综上所述，我们的研究结果证实了内源性 NOP 受体和紧张 N/OFQ 功能在束缚引起的心理应激反应中的重要作用。
