Department of Physiology, Faculty of Medicine, Université de Montréal, CP 6128, Succursale Centre-ville, Montréal, QC H3C 3J7, Canada.
Behav Brain Res. 2013 Mar 15;241:17-26. doi: 10.1016/j.bbr.2012.11.032. Epub 2012 Dec 3.
While brain kinin B(1) receptor (B(1)R) is virtually absent in control rats, it contributes to hypertension via a midbrain dopaminergic (DA) mechanism in spontaneously hypertensive rat (SHR) and Angiotensin II (Ang II)-induced hypertension. This study aims at determining whether B(1)R can also affect stereotypic nocifensive behavior through DA and/or other neuromediators in the same models. The selective B(1)R agonist Sar[D-Phe(8)][des-Arg(9)]BK was injected i.c.v. (1 μg/site) to freely behaving SHR (16 weeks), Ang II-hypertensive rats (200 ng/kg/min × 2 weeks, s.c.) and control Wistar-Kyoto rats (WKY). Behavioral activity to the agonist was measured before and after treatment with receptor antagonists (10 μg/site i.c.v. or otherwise stated) for B(1) (SSR240612), tachykinin NK(1) (RP67580), glutamate NMDA (DL-AP5), DA D(1) (SCH23390, 0.2mg/kg s.c.) and D(2) (Raclopride, 0.16 mg/kg s.c.). Other studies included inhibitors (10 μg/site) of NOS (l-NNA) and iNOS (1400W). The possible desensitisation of B(1)R upon repeated intracerebral stimulation was also excluded. B(1)R expression was measured by qRT-PCR in selected areas and by immunohistochemistry in the ventral tegmental area. Results showed that the B(1)R agonist had no effect in WKY, yet it induced nocifensive behavioral manifestations in both models of hypertension (face washing, sniffing, head scratching, rearing, teeth chattering, grooming, digging, licking, wet-dog shakes). These responses were prevented by all antagonists and inhibitors tested, but 1400 W had a less inhibitory effect on most behaviors. Compared with WKY, B(1)R mRNA levels were markedly enhanced in hypothalamus, ventral tegmental area and nucleus accumbens of SHR and Ang II-treated rats. B(1)R was detected on DA neuron of the ventral tegmental area in SHR. Data suggest that kinin B(1)R is upregulated in midbrain DA system in hypertensive rats and its i.c.v. activation induced stereotypic nocifensive behavior that is mediated by several mediators, notably substance P, glutamate, DA and NO.
虽然在正常大鼠中几乎不存在脑激肽 B(1) 受体（B(1)R），但它通过中脑多巴胺能（DA）机制在自发性高血压大鼠（SHR）和血管紧张素 II（Ang II）诱导的高血压中导致高血压。本研究旨在确定 B(1)R 是否也可以通过相同模型中的 DA 和/或其他神经递质影响刻板的伤害性行为。选择性 B(1)R 激动剂 Sar[D-Phe(8)][des-Arg(9)]BK 被注射到自由活动的 SHR（16 周）、Ang II 高血压大鼠（200ng/kg/min×2 周，皮下注射）和对照 Wistar-Kyoto 大鼠（WKY）的侧脑室（1μg/部位）。在使用受体拮抗剂（10μg/部位侧脑室注射或另有说明）治疗之前和之后，测量了对激动剂的行为活性，用于 B(1)（SSR240612）、速激肽 NK(1)（RP67580）、谷氨酸 NMDA（DL-AP5）、DA D(1)（SCH23390，0.2mg/kg 皮下注射）和 D(2)（Raclopride，0.16mg/kg 皮下注射）。其他研究包括 NOS（l-NNA）和 iNOS（1400W）抑制剂（10μg/部位）。还排除了重复脑内刺激对 B(1)R 脱敏的可能性。通过 qRT-PCR 在选定的区域测量 B(1)R 的表达，并通过免疫组织化学在腹侧被盖区测量 B(1)R 的表达。结果表明，B(1)R 激动剂在 WKY 中没有作用，但在两种高血压模型中都诱导了伤害性行为表现（洗脸、嗅探、抓头、仰头、牙齿嘎嘎作响、梳理、挖掘、舔舐、湿狗抖动）。这些反应被所有测试的拮抗剂和抑制剂所阻止，但 1400W 对大多数行为的抑制作用较小。与 WKY 相比，SHR 和 Ang II 处理大鼠的下丘脑、腹侧被盖区和伏隔核中的 B(1)R mRNA 水平明显升高。在 SHR 的腹侧被盖区的 DA 神经元上检测到 B(1)R。数据表明，激肽 B(1)R 在高血压大鼠的中脑 DA 系统中上调，其侧脑室激活诱导了刻板的伤害性行为，该行为由几种介质介导，特别是 P 物质、谷氨酸、DA 和 NO。
