Pharmacological studies investigating the mechanisms controlling the peptidergic neurotransmitter release.

药理学研究研究控制肽能神经递质释放的机制。

• 批准号: 09670093
• 负责人: NAKATA Yoshihiro
• 金额: $ 2.05万
• 依托单位: HIROSHIMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670093/
• 关键词: substance P; primary afferent neuron; cultured rat spinal dorsal root ganglion cell; substance P release; nerve growth factor; preprotachykinin mRNA; interleukin-1 beta; cyclooxygenase-2; PPTmRNA; 遊離

Substance P (SP) in a dorsal root ganglion (DRG) is involved in one of the mechanisms responsible for the transmission of noxious stimuli. To elucidate the mechanisms controlling the release of this peptidergic neurotransmitter, the effects of neurotrophins or interleukin-1beta (IL-1beta) on SP synthesis and release were examined in primary cultured rat DRG cells.Nerve growth factor (NGF) increased SP content and it's precursor, preprotachykinin (PPT) mRNA in the DRG cells. Another neurotrophins tested, brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3) had no effects on the SP content. High concentration of KCl (30mM) or capsaicin evoked the SP release from the cultured rat DRG cells in a Ca^<2+> dependent manner. IL-1beta is one of the cytokines which are synthesized and released from immune cells and considered to be important mediators during inflammation and hyperalgesia. When recombinant mouse IL-1beta was added to the DRG cells in the presence of NGF, IL-1beta evoked the SP release after 3 hours and increased SP content and PPT mRNA after 7 days. The effect of IL-1beta on the SP release was Ca^<2+> dependent and significantly inhibited by a IL-1 receptor antagonist and cyclooxygenase inhibitors, aspirin, indomethacin, NS-398 or dexamethasone. Furthermore IL-1beta increased inducible cyclooxygenase (COX)-2 mRNA without any effects on constitutive COX-1 mRNA in the incubation of 1 hour.Thus, it is suggested that IL-1beta evoked the release of this nociceptive neuropeptide in the DRG cells via specific IL-1 receptors, the mechanisms of which might be involved in prostanoid systems. It could be responsible for the hyperalgesic action with reference to inflammatory pain in primary afferent neuron to spinal cord pathway.

背根神经节（DRG）内的P物质（SP）参与了伤害性刺激的传递。为阐明这种肽能神经递质释放的调控机制，在原代培养的大鼠DRG细胞上观察了神经营养素和白细胞介素1 β（IL-1 β）对SP合成和释放的影响。另一种神经营养因子，脑源性神经营养因子（BDNF）或神经营养因子-3（NT-3）对SP含量没有影响。高浓度KCl（30 mM）或辣椒素以Ca^2+依赖的方式诱导培养的大鼠DRG细胞释放SP。IL-1 β是由免疫细胞合成和释放的细胞因子之一，被认为是炎症和痛觉过敏过程中的重要介质。重组小鼠IL-1 β与NGF共同作用于DRG细胞后，3 h后可引起SP释放，7 d后SP含量和PPT mRNA表达增加。IL-1 β对SP释放的作用是Ca^<2+>依赖性的，并且可被IL-1受体拮抗剂和环氧合酶抑制剂阿司匹林、吲哚美辛、NS-398或地塞米松显著抑制。IL-1 β在孵育1小时后，诱导型环氧合酶（考克斯）-2 mRNA表达增加，而对组成型考克斯-1 mRNA表达无影响，提示IL-1 β通过特异性IL-1受体诱导DRG细胞释放这种伤害性神经肽，其机制可能与前列腺素系统有关。它可能与初级传入神经元到脊髓通路的炎性痛有关。

项目成果

A Inoue et al.: "Effects of neurotrophins or interleukin-1 beta on substance P synthesis in cultured rat dorsal root ganglia" Neurochemical Research. 24(1). 153 (1999)

A Inoue 等人：“神经营养素或白细胞介素 1β 对培养大鼠背根神经节 P 物质合成的影响”神经化学研究。

A Inoue et al.: "Effects of neurotrophins or interleukin-1β on substance P synthesis in cultured rat dorsal root ganglia" Neurochemical Research. 24(1). 153 (1999)

A Inoue 等人：“神经营养素或白细胞介素 1β 对培养大鼠背根神经节 P 物质合成的影响”《神经化学研究》24(1)。