Molecular biological and pharmacological study on the roles of brain interleukin-1 in transmission and regulation of nociceptive information

在本研究中，我们进行了以下实验来阐明大脑白细胞介素-1β在伤害性信息调节中的作用。首先，脑室内给予IL-1β并测量机械刺激的伤害性阈值。较低剂量（10,000 pg）的 IL-1beta 会引起痛觉过敏，但较高剂量（1,10 ng）的 IL-1beta 会引起镇痛。 IL-1β对伤害性阈值的这些作用可通过同时给予IL-1受体拮抗剂来抑制。水杨酸钠预处理可抑制低剂量IL-1β引起的痛觉过敏，但不抑制高剂量IL-1β引起的镇痛作用。 α-螺旋-CRF 的预处理抑制了 IL-1β 的痛觉过敏和镇痛作用。其次，我们利用原位杂交技术检测了大鼠脑中IL-1受体mRNA的分布。在丘脑、杏仁核和髓质的几个核中观察到I型IL-1受体mRNA。在这些细胞核中，I型IL-1受体mRNA定位于表达神经元特异性烯醇化酶mRNA的神经元细胞上。在正常大鼠脑中未观察到II型IL-1受体mRNA。至于IL-1β转化酶，它是加工IL-1β前体蛋白产生成熟IL-1β的关键酶，在正常大鼠脑中未检测到其mRNA。此外，异丙肾上腺素的给药已被证明可以在大鼠下丘脑中诱导IL-1β mRNA，给药后1小时引起多个脑区域中IL-1β mRNA的显着表达。此外，还观察到异丙肾上腺素的镇痛作用。最后，在腹腔注射福尔马林后，在下丘脑中观察到 IL-1β mRNA 的表达增加，从而引起持续的疼痛。这些数据强烈表明 IL-1β 参与大脑中伤害性信息的调节。

In this study, we conducted the following expeiments to elucidate the roles of brain interleukin-1beta in the modulation of nociceptive information. First, IL-1beta was intracerebroventriculary administrated and the nociceptive threshold to mechanical stimulation was measured. The lower doses (10,000 pg) of IL-1beta induced hyperalgesia, but the higher doses (1,10 ng) of IL-1beta induced analgesia. These effects of IL-1beta on the nociceptive threshold were inhibited by the simultaneous administration of IL-1 receptor antagonist.Hyperalgesia induced by the lower dose of IL-1beta but not analgesic effects by the higher dose of IL-1beta, was suppressed by pretreatment of sodium salicylate. Pretreatment of alpha-helical-CRF inhibited both hyperalgesic and analgesic effects of IL-1beta. Secondly, we examined the distribution of IL-1 receptor mRNA in the rat brain using in situ hybridization technique. Type I IL-1 receptor mRNA was observed in the several nuclei of the thalamus, amygdala and medulla. In these nuclei type I IL-1 receptor mRNA was localized on the neuronal cells which express neuron specific enolase mRNA.Type II IL-1 receptor mRNA was not observed in the normal rat brain. As regard for IL-1beta converting enzyme , a key enzyme for processing the IL-1beta precursor protein to produce mature IL-1beta, its mRNA was not detected in the normal rat brain. Furthermore, an administration of isoproterenol, which had been shown to induce IL-1beta mRNA in the rat hypothalamus, caused significant expression of IL-1beta mRNA at 1 hr after administration in several brain regions. In addition, analgesic effects of isoproterenol were observed. Lastly, increased expression of IL-1beta mRNA was observed in the hypothalamus after i.p.l.administration of formalin, which induced sustained pain. These data strongly suggest that IL-1beta is involved in the regulation of nociceptive information in the brain.