Laorden Maria Luisa, Castells Maria Teresa, Milanés Maria Victoria
Equip of Cellular and Molecular Pharmacology, University School of Medicine, 30100 Murcia, Spain.
Br J Pharmacol. 2002 May;136(1):67-75. doi: 10.1038/sj.bjp.0704684.
Different data support a role for brainstem noradrenergic inputs to the hypothalamic paraventricular nucleus (PVN) in the control of hypothalamus - pituitary - adrenocortical (HPA) axis. However, little is known regarding the functional adaptive changes of noradrenergic afferent innervating the PVN and supraoptic nucleus (SON) during chronic opioid exposure and upon morphine withdrawal. Here we have studied the expression of Fos after administration of morphine and during morphine withdrawal in the rat hypothalamic PVN and SON. Fos production was also studied in brainstem regions that innervate hypothalamic nuclei: the nucleus of solitary tract (NTS - A2) and the ventrolateral medulla (VLM - A1) and combined with immunostaining for tyrosine hydroxylase (TH) for immunohistochemical identification of active neurons during morphine withdrawal. Male rats were implanted with s.c. placebo or morphine (tolerant/dependent) pellets for 7 days. On day 8 rats received an injection of saline i.p., morphine i.p., saline s.c. or naloxone s.c. Acute morphine administration produced an increase in Fos expression at hypothalamic nuclei and in the brainstem regions, and tolerance developed towards this effect. Precipitated morphine withdrawal induced marked Fos immunoreactivity within the PVN and SON. Concomitantly, numerous neurons in the brainstem were stimulated by morphine withdrawal. Moreover, catecholaminergic-positive neurons in the brainstem showed a significant increase in Fos expression in response to morphine withdrawal. These findings demonstrate that chronic activation of opioid receptors results in altered patterns of immediate-early genes (IEG) expression in the PVN and SON, which occurs concurrently with an increased activity of their inputs from the brainstem.
不同的数据支持脑干去甲肾上腺素能输入至下丘脑室旁核（PVN）在控制下丘脑 - 垂体 - 肾上腺皮质（HPA）轴中发挥作用。然而，关于慢性阿片类药物暴露及吗啡戒断期间支配PVN和视上核（SON）的去甲肾上腺素能传入神经的功能适应性变化，我们知之甚少。在此，我们研究了大鼠下丘脑PVN和SON在给予吗啡后及吗啡戒断期间Fos的表达。还研究了支配下丘脑核团的脑干区域：孤束核（NTS - A2）和延髓腹外侧区（VLM - A1）中Fos的产生，并结合酪氨酸羟化酶（TH）免疫染色，用于在吗啡戒断期间对活跃神经元进行免疫组化鉴定。雄性大鼠皮下植入安慰剂或吗啡（耐受/依赖）丸剂7天。在第8天，大鼠腹腔注射生理盐水、腹腔注射吗啡、皮下注射生理盐水或皮下注射纳洛酮。急性给予吗啡使下丘脑核团和脑干区域的Fos表达增加，且对这种效应产生了耐受性。诱发的吗啡戒断在PVN和SON内诱导出明显的Fos免疫反应性。同时，吗啡戒断刺激了脑干中的大量神经元。此外，脑干中儿茶酚胺能阳性神经元对吗啡戒断的反应表现为Fos表达显著增加。这些发现表明，阿片受体的慢性激活导致PVN和SON中即刻早期基因（IEG）表达模式改变，这与来自脑干的输入活动增加同时发生。
