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

阐明从免疫系统到神经系统的信号传递机制-使用炎性疼痛模型

• 批准号: 12671497
• 负责人: IBUKI Takae
• 金额: $ 2.24万
• 依托单位: Kyoto Prefectural University of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671497/
• 关键词: inflammation; vascular endthelial cells; cycloxygenase-2; prostaglandin; hyperalgesia; cytokine; PGE_2 synthesizing enzyme; central sensitization; 炎症性サイトカイン; プロスタグランディン; PGE合成酵素; シクロオキシゲナーゼ; 炎症性疼痛

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

我们研究了免疫系统向神经系统的信号传递机制，重点是前列腺素（PGs）。在炎症早期，由炎症部位的大相细胞或单核细胞合成的PGs通过敏感感觉神经末梢参与炎症性痛觉过敏。在炎症部位预防性给予PG合成限速酶环氧化酶-2 （OOX-2）选择性抑制剂可有效预防痛觉过敏。然后，在炎症的中后期，我们得到了以下结果：1)脑脊液（CSF）中PGE_2浓度显著升高；2)全身给药OOX-2抑制剂是在炎症的中期，而不是在炎症开始前；3)鞘内注射OOX-2抑制剂即使在小剂量下也能减轻痛觉过敏；4)减轻痛觉过敏程度。另外，OOX-2的表达与CSF中PGE_2的浓度有很好的相关性。进一步鉴定了PGE_2在中枢神经系统（CNS）中的合成细胞；1) PGE_2合成酶（PGES）与中枢神经系统血管内皮细胞共定位；2)OOK-2和PGES在血管内皮细胞中共定位，共定位比例均大于90%；3)这些表达OOK-2和PGES-的内皮细胞广泛分布于脑和脊髓，无区域差异。这些观察结果与OOX-2表达的传统理论相矛盾，也与OOX-2表达和PGE_2合成发生在神经元中的传统理论相矛盾。全身症状伴有外周炎症，如发热、全身乏力、痛觉过敏。此外，我们还提出了新的全身性症状理论，为阐明全身性症状的发病机制提供了有力的线索，同时也为阐明伴有发热、全身乏力、炎症部位向中枢神经系统信号传递等周围性炎症的全身性症状的发病机制提供了有力的线索，这是基于血管内皮细胞一旦细胞因子与细胞因子受体结合就会合成PGE_2；外周部位产生的促炎细胞因子参与了信号向血管内皮细胞的体液传递。我们得到了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

项目成果

Ueda M: "Foot hyperalgesia after thoracic burn injury-Histochemical, behavioral and pharmacological studies-"Acta Histochem.Cytochem. 34(6). 441-450 (2001)

上田 M：“胸部烧伤后足部痛觉过敏 - 组织化学、行为和药理学研究 -”Acta Histochem.Cytochem。

Masashi Ueda, Munetaka Hirose, Nobuyuki Takei, Takae Ibuki, Yoshihisa Naruse, Fumimasa Amaya, Yasuhiko Ibata, Masaki Tanaka: "Nerve growth factor induces systemic hyperalgesia after thoracic burn injury in the rat"Neuroscience Letters. 328. 97-100 (2002)

Masashi Ueda、Munetaka Hirose、Nobuyuki Takei、Takae Ibuki、Yoshihisa Naruse、Fumimasa Amaya、Yasuhiko Ibata、Masaki Tanaka：“神经生长因子在大鼠胸部烧伤后诱导全身性痛觉过敏”《神经科学快报》。

Takae Ibuki, Martin Marsala, Takashi Masuyama and Tony L.Yaksh: "Spinal Amino Acid Release and Repeated Withdrawal in Spinal Morphine Tolerant Rats"British Journal of Pharmacology. 138. 689-697 (2003)

Takae Ibuki、Martin Marsala、Takashi Masuyama 和 Tony L.Yaksh：“脊髓吗啡耐受大鼠的脊髓氨基酸释放和反复戒断”英国药理学杂志。

Masashi Ueda: "Nerve growth factor induces systemic hyperalgesia after thoracic burn injury in the rat"Neuroscience Letters. 328. 97-100 (2002)

Masashi Ueda：“神经生长因子在大鼠胸部烧伤后诱导全身痛觉过敏”《神经科学快报》。

M.Namba: "Role Of Peripheral Prostaglandin Synthesis In Inflammatory Hyperalgesia"Society for Neuroscience. Program No.47.2(CD-ROM). (2002)

M.Namba：“外周前列腺素合成在炎症性痛觉过敏中的作用”神经科学学会。