Pharmacological studies investigating the mechanisms controlling the peptidergic neurotransmitter release.

背根神经节(DRG)中的P物质(SP)参与伤害性刺激的传递。为了阐明这种肽能神经递质释放的调控机制，我们观察了神经营养因子和白介素1β(IL-1β)对原代培养的大鼠背根神经节细胞SP合成和释放的影响。神经生长因子(NGF)可增加DRG细胞内P物质及其前体速激肽原(PPT)mRNA的含量。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含量无影响。高浓度KCl(30 MM)或辣椒素以钙依赖的方式诱导培养的大鼠背根神经节细胞释放SP。IL-1β是由免疫细胞合成和释放的一种细胞因子，被认为是炎症和痛觉过敏过程中的重要介质。当重组小鼠IL-1β加入含有NGF的DRG细胞中时，IL-1β在3h后可引起细胞内P物质的释放，7d后可使细胞内P物质含量和PPT基因表达增加。IL-1β对SP释放的影响是钙依赖性的，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。此外，IL-1β作用1h可增加诱导型环氧合酶(COX)-2mRNA的表达，但对COX-1mRNA的表达无影响，提示IL-1β可通过特异性的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至脊髓通路的炎性痛有关的痛敏作用有关。

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.