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

我们研究了从免疫系统到神经系统的信号传递机制，重点是前列腺素(PGs)。炎症早期，炎症部位的大相或单核细胞合成的前列腺素，通过感觉神经末梢的感觉参与炎性痛敏反应。炎症部位预防性给予PG合成限速酶环氧合酶-2抑制物(OOX-2)，可有效预防痛觉过敏。在炎症的中后期，我们得到了以下结果：1)脑脊液中前列腺素E_2的浓度显著升高；2)在炎症的中期而不是在炎症发生之前，全身应用氧化氧合酶-2抑制剂，既抑制了炎性痛觉过敏，又抑制了脑脊液中前列腺素E_2的升高；3)鞘内注射氧化氧合酶-2抑制剂，即使是小剂量的痛觉过敏也能减轻痛觉过敏4)…IA、OOX-2的表达与脑脊液中PGE_2浓度呈正相关。此外，还鉴定了中枢神经系统中的前列腺素E_2合成细胞：1)前列腺素E_2合成酶(PGE_2)，中枢神经系统中的血管内皮细胞；2)OOK-2和PGE共同定位于血管内皮细胞，共定位的比例超过90%；3)表达OOK-2和PGE的内皮细胞广泛分布于脑和脊髓，没有地域差异。这些结果与传统的OOX-2表达理论和OOX-2表达和PGE_2合成发生在神经元的传统理论相矛盾。我们的全身症状伴随着外周炎症，如发烧、全身疲劳、痛觉过敏。此外，我们得到了新的全身性症状理论将是阐明全身性症状发病机制的有力线索，以及阐明全身性症状伴随外周炎症的发病机制的有力线索，如发热、全身疲劳、从炎症部位到中枢神经系统的信号传递，这是基于以下事实：一旦细胞因子与其上的细胞因子受体结合，血管内皮细胞合成PGE_2；外周产生的促炎细胞因子体液参与到血管内皮细胞的信号传递。目前有关细胞因子参与信号传递的研究已有初步结果，其作用机制尚需进一步研究。

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