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脑白细胞介素-1 β在伤害性信息调制中的作用。首先，侧脑室注射IL-1 β，测定机械刺激的伤害性阈值。低剂量（10，000 pg）的IL-1 β诱导痛觉过敏，但高剂量（1，10 ng）的IL-1 β诱导镇痛。同时给予IL-1受体拮抗剂可抑制IL-1 β对痛阈的影响，水杨酸钠预处理可抑制低剂量IL-1 β引起的痛敏，但不能抑制高剂量IL-1 β的镇痛作用。α螺旋CRF预处理可抑制IL-1 β的痛觉过敏和镇痛作用。其次，我们用原位杂交技术检测了IL-1受体mRNA在大鼠脑内的分布。I型IL-1受体mRNA在丘脑、杏仁核和延髓的几个核团中观察到。在这些核团中，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，而在正常大鼠脑中未见II型IL-1受体mRNA。至于IL-1 β转化酶，一种加工IL-1 β前体蛋白产生成熟IL-1 β的关键酶，其mRNA在正常大鼠脑中未检测到。此外，异丙肾上腺素给药（已显示可诱导大鼠下丘脑中的IL-1 β mRNA）在给药后1小时在几个脑区引起IL-1 β mRNA的显著表达。此外，还观察了异丙肾上腺素的镇痛作用。最后，在腹腔注射福尔马林后，观察到下丘脑中IL-1 β mRNA的表达增加，这引起了持续的疼痛。这些数据有力地表明，IL-1 β参与了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.