Elucidation of signal transmission Mechanism from the immune system to the nervous system -Using the inflammatory pain model

本研究主要以前列腺素（PGs）为研究对象，探讨了免疫系统向神经系统的信号传递机制。在炎症早期，炎症部位的巨噬细胞或单核细胞合成的PGs通过敏感感觉神经末梢参与炎性痛敏。在炎症部位预防性给予环氧合酶-2（OOX-2）（PG合成的限速酶）选择性抑制剂可有效预防痛觉过敏。在炎症的中晚期，我们得到以下结果：1）脑脊液（CSF）中PGE_2的浓度显著升高; 2）全身应用OOX-2抑制剂是在炎症的中期，而不是在炎症发生之前，鞘内注射OOX-2抑制剂可抑制炎性痛敏和CSF中PGE_2的升高，即使在小剂量时也能减轻痛敏超藻度 ...更多信息 Ia、OOX-2表达与CSF中PGE_2浓度呈显著正相关。此外，还鉴定了中枢神经系统（CNS）的PGE_2合成细胞; 1）PGE_2合成酶（PGES）; 2）OOK-2和PGES共定位于血管内皮细胞，共定位率达90%以上; 3）OOK-2和PGES-2共定位于血管内皮细胞，共定位率达90%以上。表达内皮细胞广泛分布于脑和脊髓，无区域性差异。这些观察结果与OOX-2表达的传统理论相矛盾，与OOX-2表达和PGE_2合成发生在神经元中的传统理论相矛盾。我们的全身症状伴有外周炎症，如发热、全身乏力、痛觉过敏。此外，我们还得到了新的全身症状理论将是阐明全身症状的发病机制的有力线索，同时也是阐明全身症状伴有外周炎症如发热、全身乏力、从炎症部位到中枢神经系统的信号传递基于血管内皮细胞合成PGE_2的事实。2细胞因子一旦与其上的细胞因子受体结合，在外周部位产生的促炎细胞因子参与体液信号传递到血管内皮细胞。我们得到了关于细胞因子参与信号传递的初步结果，需要进一步的研究来完全阐明其机制。

We in vestigated the signal tran smission mechanism from the immune system to the nervous system focusing on prostaglandins (PGs). In the early phase of the inflammation, PGs synthesized by macrophases or monocytes at the inflammatory saite, is involved in the inflammatory hyperalgesia by sen sitizing the sensory nerve terminals. The prophylactic administration of selective inhibitor of cyclooxygenase-2 (OOX-2), rate limiting enzyme of PG synthesis, at the inflammatory site was effective in preventing hyperalgesia. Then, in the intermediate to later phase of the inflammation, we got the following results 1) the concentration of PGE_2 in the cerebrospinal fluid (CSF) in creased significantly 2) systemic administration of OOX-2 inhibitor in the intermediate phase, not before the inflammatory on set, suppressed both inflammatory hyperalgesia and the increase in PGE_2 in the CSF 3) intrathecal injection of OOX-2 inhibitor alleviated hyperalgesia even at a small dose 4) degree of hyperalges … More ia, OOX-2 expression and the concentration of PGE_2 in the CSF correlated very well. Furthermore, PGE_2 synthesizing cell in the central nervous system (CNS) was identified; 1) PGE_2 synthesizing enzyme (PGES), the vascular endothelial cells in the CNS 2) OOK-2 and PGES colocalized in the vascular endothelial cell and the percentage of colocalization was more than 90% 3) these OOK-2- and PGES- expressing endothelial cells widely distributed in the brain and the spinal cord without regional differences. These observations are contradictory to the conventional theory that OOX-2 expression are contradictory to the conventional theory that OOX-2 expression and PGE_2 synthesis occur in the neurons. Our systemic symptoms accompanied by peripheral inflammation such as fever up, general fatigue, hyperalgesia. Furthermore, we have got the novel theory of systemic symptoms would be the potent clue to clarify the pathogenesis of systemic symptons accompanied by the potent clue to clarify the pathogenesis of systemic symptoms accompanied by peripheral inflammation such as fever up, general fatigue, signal transmission from theinflammatory site to the CNS based on the fact that vascular endothelial cells synthesize PGE_2 once cytokines bind to cytokine receptors on them; proinflammatory cytokines produced at the peripheral site is involved in the signal transmission to vascular endothelial cells humoraly. We got the preliminary result concerning tcytokines involved in the signal transmission and further investigation is needed for the complete clarification of the mechanism Less