Laneuville O, Reader T A, Couture R
Département de Physiologie, Faculté de Médecine, Université de Montréal, Québec, Canada.
Eur J Pharmacol. 1989 Jan 17;159(3):273-83. doi: 10.1016/0014-2999(89)90158-1.
In the awake restrained rat the intrathecal (i.th.) administration of 8.1 pmol-8.1 nmol of bradykinin (BK) and kallidin (KD) enhanced the reaction time (RT) to a noxious radiant heat stimulus in a dose-dependent manner. The fragments BK-(1-8) and BK-(1-7) were active only at doses higher than 10 nmol and the following rank order of potency was observed: BK greater than KD much greater than BK-(1-8) greater than BK-(1-7). The increment of tail-flick latency was greatest at 1 (BK) or 6 (KD) min and the RT returned to basal levels within 15 min post-administration. The effect of BK (81 pmol) was unaffected by the prior i.th. administration of propranolol and naloxone but was significantly potentiated by prazosin (P less than 0.05). In contrast, the response to BK was significantly blocked (P less than 0.001) by phentolamine, idazoxan and yohimbine as well as by treatment with 6-hydroxydopamine (6-OHDA) at a dose of 20 micrograms (i.th.) 1 week earlier. The latter pretreatment reduced the antinociceptive effect of i.th. tyramine (7 mumol) and potentiated that to noradrenaline (NA) (0.6 nmol) (P less than 0.01) while it preserved both the antinociceptive effect of neurokinin B (8 nmol) and the hyperalgesic effect of substance P (6.5 nmol). A biochemical analysis revealed that 6-OHDA treatment reduced the NA content in the lumbar spinal cord by 60% without affecting the levels of serotonin, dopamine, adrenaline or their main metabolites. There were also significant reductions in NA content in cervical (44%) and thoracic (55%) spinal cord. Pretreatment with 6-OHDA for a longer survival period (2 weeks) caused a further decrease of NA in the lumbar spinal cord (88%); however, the serotonin and dopamine levels were reduced in all regions examined. These results suggest that BK (kinins) may inhibit spinal nociceptive sensory transmission and produce analgesia by acting presynaptically on terminals of bulbospinal NA-containing fibers.
在清醒拘束大鼠中，鞘内注射8.1皮摩尔至8.1纳摩尔的缓激肽（BK）和胰激肽（KD）可剂量依赖性地延长对有害热辐射刺激的反应时间（RT）。BK-(1-8)和BK-(1-7)片段仅在高于10纳摩尔的剂量时才有活性，且观察到以下效价顺序：BK＞KD＞＞BK-(1-8)＞BK-(1-7)。甩尾潜伏期的增加在1分钟（BK）或6分钟（KD）时最大，给药后15分钟内RT恢复至基础水平。BK（81皮摩尔）的作用不受预先鞘内注射普萘洛尔和纳洛酮的影响，但哌唑嗪可显著增强其作用（P＜0.05）。相反，酚妥拉明、咪唑克生和育亨宾以及1周前鞘内注射20微克剂量的6-羟基多巴胺（6-OHDA）可显著阻断对BK的反应（P＜0.001）。后一种预处理降低了鞘内注射酪胺（7微摩尔）的抗伤害感受作用，并增强了对去甲肾上腺素（NA）（0.6纳摩尔）的作用（P＜0.01），同时保留了神经激肽B（8纳摩尔）的抗伤害感受作用和P物质（6.5纳摩尔）的痛觉过敏作用。生化分析显示，6-OHDA处理使腰段脊髓中的NA含量降低了60%，而不影响5-羟色胺、多巴胺、肾上腺素或其主要代谢产物的水平。颈段（44%）和胸段（55%）脊髓中的NA含量也显著降低。6-OHDA预处理较长存活期（2周）导致腰段脊髓中NA进一步减少（88%）；然而，在所有检测区域中5-羟色胺和多巴胺水平均降低。这些结果表明，BK（激肽）可能通过对含NA的延髓脊髓纤维终末进行突触前作用来抑制脊髓伤害性感觉传递并产生镇痛作用。
