A pivotal role for enhanced brainstem Orexin receptor 1 signaling in the central cannabinoid receptor 1-mediated pressor response in conscious rats.
A pivotal role for enhanced brainstem Orexin receptor 1 signaling in the central cannabinoid receptor 1-mediated pressor response in conscious rats.
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DOI：
10.1016/j.brainres.2015.06.011
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发表时间：
2015-10-05
期刊：
影响因子：
2.9
通讯作者：
Abdel-Rahman AA
中科院分区：
文献类型：
--
作者：
Ibrahim BM;Abdel-Rahman AA
食欲素受体1（OX 1 R）信号转导与大麻素受体1（CB 1 R）调节摄食有关。此外，我们的研究建立了中央CB 1 R介导的升压反应的神经元型一氧化氮合酶（nNOS）和细胞外信号调节激酶1/2（ERK 1/2）在RVLM磷酸化的依赖性。我们验证了脑干食欲素A/OX 1 R信号在中枢CB 1 R介导的升压反应中起关键作用的新假设。我们的多重标记免疫荧光结果显示，共同定位的CB 1 R，OX 1 R和肽食欲素-A内的C1区的头端腹外侧延髓（RVLM）。脑池内（i.c.）在清醒大鼠中，WIN 55，212-2（15 µg/大鼠）导致RVLM神经元组织中BP和食欲素-A水平显著升高。其他研究确定了食欲素-A在中枢CB 1 R介导的升压反应中的因果作用，因为（i）选择性阻断中枢CB 1 R（AM 251，30 μg/大鼠; i.c.）消除WIN 55，212-2诱发的RVLM食欲素-A水平的增加，（ii）选择性OX 1 R拮抗剂SB-408124（10 nmol/大鼠; i.c.）减毒食欲素-A（3 nmol/大鼠; i.c.）或WIN 55，212-2（15 µg/大鼠; i.c.）-诱发的升压反应，而选择性CB 1 R阻断剂（AM 251）对食欲素-A（3 nmol/大鼠; i.c.）诱发的升压反应，（iii）RVLM中的直接CB 1 R激活（WIN 55，212-2; 0.1 µg/rat）增加RVLM食欲素A和BP。最后，SB-408124减弱了WIN 55，212-2诱发的RVLM nNOS和ERK 1/2磷酸化和BP的增加。我们的研究结果表明，orexin-A/OX 1 R依赖性激活RVLM nNOS/ERK 1/2级联反应是中枢CB 1 R介导的升压反应在清醒大鼠的重要神经化学机制。
Orexin receptor 1 (OX1R) signaling is implicated in cannabinoid receptor 1 (CB1R) modulation of feeding. Further, our studies established the dependence of the central CB1R-mediated pressor response on neuronal nitric oxide synthase (nNOS) and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation in the RVLM. We tested the novel hypothesis that brainstem orexin-A/OX1R signaling plays a pivotal role in the central CB1R-mediated pressor response. Our multiple labeling immunofluorescence findings revealed co-localization of CB1R, OX1R and the peptide orexin-A within the C1 area of the rostral ventrolateral medulla (RVLM). Activation of central CB1R following intracisternal (i.c.) WIN55,212-2 (15 µg/rat) in conscious rats caused significant increases in BP and orexin-A level in RVLM neuronal tissue. Additional studies established a causal role for orexin-A in the central CB1R-mediated pressor response because (i) selective blockade of central CB1R (AM251, 30 µg/rat; i.c.) abrogated WIN55,212-2-evoked increases in RVLM orexin-A level, (ii) the selective OX1R antagonist SB-408124 (10 nmol/rat; i.c.) attenuated orexin-A (3 nmol/rat; i.c.) or WIN55,212-2 (15 µg/rat; i.c.)-evoked pressor response while selective CB1R blockade (AM251) had no effect on orexin-A (3 nmol/rat; i.c.)-evoked pressor response, (iii) direct CB1R activation in the RVLM (WIN55,212-2; 0.1 µg/rat) increased RVLM orexin-A and BP. Finally, SB-408124 attenuated WIN55,212-2-evoked increases in RVLM nNOS and ERK1/2 phosphorylation and BP. Our findings suggest that orexin-A/OX1R dependent activation of the RVLM nNOS/ERK1/2 cascade is essential neurochemical mechanism for the central CB1R–mediated pressor response in conscious rats.