Baraban S C, Stornetta R L, Guyenet P G
Department of Pharmacology, University of Virginia, Charlottesville 22908, USA.
Brain Res. 1995 Apr 10;676(2):245-57. doi: 10.1016/0006-8993(95)00097-a.
In urethane anesthetized rats, iontophoretic application of morphine or alpha-methylnoradrenaline (alpha-MNE) inhibited (80-100%) the discharges of all putative adrenergic (C1) cells of the rostral ventrolateral medulla (RVLM). The effect of morphine was blocked selectively by naloxone while that of alpha-MNE was blocked selectively by the alpha 2-adrenergic antagonist idazoxan. Putative C1 cells were inhibited (75-100%) by low i.v. doses of clonidine (10-15 micrograms/kg). Most cells (7/10) were also inhibited by morphine i.v. (81% at 7 mg/kg). Two cells were slightly excited at doses below 2 mg/kg and inhibited at higher doses. Three cells were excited only. All effects of morphine i.v. were reversed by naloxone (1 mg/kg, i.v.). Intravenous administration of naloxone to morphine-dependent rats increased significantly the firing rate of all putative C1 adrenergic cells (from 5.8 +/- 0.9 spikes/s to 12.3 +/- 1.5 spikes/s; n = 8). During withdrawal these cells could still be inhibited (80-100%) by i.v. injection of clonidine (15 micrograms/kg). C-Fos expression induced by naltrexone-precipitated withdrawal was examined in the brainstem of freely moving morphine-dependent rats pretreated with clonidine or saline before injection of the opioid antagonist. The locus coeruleus (LC) of the same rats was examined for comparison. Morphine withdrawal without clonidine treatment significantly increased the number of Fos-like-immunoreactive (Fos-LIR) cells in the RVLM and LC. Clonidine pretreatment (1 mg/kg, i.p.) reduced the number of withdrawal-activated Fos-LIR cells in LC by 81%. In the RVLM this reduction averaged 37% for all cell types and 48% for C1 adrenergic cells. Further, a very large proportion of RVLM neurons that expressed c-Fos during morphine withdrawal (83%) were immunoreactive for alpha 2A-adrenergic receptors. This study suggests that, like noradrenergic cells of the LC, C1 adrenergic neurons of the RVLM are: (i) inhibited by both opiate and alpha 2-adrenergic receptor agonists; and (ii) activated during naloxone-precipitated morphine withdrawal. Since C1 cells are considered essential to sympathetic tone generation, their inhibition by morphine may contribute to the hypotensive effects of this opioid agonist in non-dependent individuals. Their excitation during opiate withdrawal may also contribute to the autonomic activation that characterizes this syndrome. Finally, inhibition of C1 cells by clonidine may contribute to the clinically recognized efficacy of this drug to attenuate autonomic signs of opiate withdrawal.
在氨基甲酸乙酯麻醉的大鼠中，离子导入吗啡或α-甲基去甲肾上腺素（α-MNE）可抑制（80 - 100%）延髓头端腹外侧区（RVLM）所有假定的肾上腺素能（C1）细胞的放电。吗啡的作用可被纳洛酮选择性阻断，而α-MNE的作用可被α₂肾上腺素能拮抗剂咪唑克生选择性阻断。低静脉注射剂量的可乐定（10 - 15微克/千克）可抑制（75 - 100%）假定的C1细胞。大多数细胞（7/10）也可被静脉注射的吗啡抑制（7毫克/千克时为81%）。2个细胞在低于2毫克/千克的剂量下略有兴奋，而在较高剂量下被抑制。3个细胞仅表现为兴奋。静脉注射吗啡的所有作用均被纳洛酮（1毫克/千克，静脉注射）逆转。对吗啡依赖大鼠静脉注射纳洛酮可显著提高所有假定的C1肾上腺素能细胞的放电频率（从5.8±0.9次/秒增至12.3±1.5次/秒；n = 8）。在戒断期间，这些细胞仍可被静脉注射可乐定（15微克/千克）抑制（80 - 100%）。在自由活动的吗啡依赖大鼠的脑干中，检测了纳曲酮诱发戒断所诱导的C-Fos表达，这些大鼠在注射阿片类拮抗剂之前用可乐定或生理盐水预处理。同时检测了同一只大鼠的蓝斑（LC）以作比较。未用可乐定治疗的吗啡戒断显著增加了RVLM和LC中Fos样免疫反应性（Fos-LIR）细胞的数量。可乐定预处理（1毫克/千克，腹腔注射）使LC中戒断激活的Fos-LIR细胞数量减少了81%。在RVLM中，所有细胞类型的这种减少平均为37%，C1肾上腺素能细胞为48%。此外，在吗啡戒断期间表达c-Fos的RVLM神经元中，很大一部分（83%）对α₂A肾上腺素能受体具有免疫反应性。本研究表明，与LC的去甲肾上腺素能细胞一样，RVLM的C1肾上腺素能神经元：（i）被阿片类药物和α₂肾上腺素能受体激动剂抑制；（ii）在纳洛酮诱发的吗啡戒断期间被激活。由于C1细胞被认为是产生交感神经张力所必需的，吗啡对它们的抑制作用可能导致这种阿片类激动剂在非依赖个体中的降压作用。它们在阿片类药物戒断期间的兴奋也可能导致该综合征所特有的自主神经激活。最后，可乐定对C1细胞的抑制作用可能有助于该药物在临床上公认的减轻阿片类药物戒断自主神经症状的疗效。
