Synergistic interaction of nerve growth factor and glial cell-line derived neurotrophic factor in muscular mechanical hyperalgesia in rats
Synergistic interaction of nerve growth factor and glial cell-line derived neurotrophic factor in muscular mechanical hyperalgesia in rats
复制标题
神经生长因子和胶质细胞源性神经营养因子在大鼠肌肉机械痛觉过敏中的协同相互作用
DOI：
10.1113/jp280683
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
and Kazue Mizumura.
中科院分区：
文献类型：
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作者：
Shiori Murase;Kimiko Kobayashi;Teruaki Nasu;Chiaki Kihara;Toru Taguchi;and Kazue Mizumura.
神经生长因子(NGF)和胶质细胞源性神经营养因子(GDNF)是胚胎神经元发育和存活所必需的。然而，在出生后，它们在许多疼痛条件下痛觉过敏的产生中起着关键作用。这两种因素被认为作用于不同的初级传入细胞组，但它们之间的相互作用尚未被研究。这里我们展示了这两个因素之间的协同效应。肌肉注射两种因子在低浓度下单独作用不起作用，可诱导大鼠肌肉机械性痛觉过敏。我们发现在初级传入神经元中存在协同作用，并发现约25%支配肌肉的初级传入同时表达TrkA(神经生长因子受体)和GFRGDNF1(α受体)。我们的药理学手段表明，含有TrkA和GfRGDNF1的传入神经元同时表达TRPV1和ASIC。我们的数据为神经生长因子和胶质细胞源性神经营养因子在某些炎症条件下表达上调并在诱导痛觉过敏中发挥关键作用奠定了基础。然而，它们之间的相互作用还没有得到研究。我们研究了两种神经营养因子在SD大鼠中是否以及在哪里发生了相互作用。腓肠肌注射神经生长因子(0.1m)和神经营养因子(0.008µm)的混合物，可引起明显的机械痛敏反应(F(6，30)=613.62，P=0.0001)，两者之间存在协同作用。注射该混合物后，背根节受压诱导的磷酸化细胞外信号调节激酶(PERK)免疫反应增强(与PBS相比，P=0.0.028)，神经生长因子和胶质细胞源性神经营养因子可在初级传入水平发生相互作用。原位杂交结果显示，23.7%~29.2%的GC-DRG神经元共表达TrkA(神经生长因子受体)和GfRGDNF1(α受体)。共表达的GC-DRG神经元的细胞大小不向小范围倾斜，而是广泛分布于小到大的范围。因此，一些与细小轴突共表达的神经元被认为与这种机械性痛敏有关。阿米洛利(F(1，13)=0.5.056，P=0.0.0425)和卡萨西平(F(1，10)=0.8.402，P=0.0.0159，与二甲基亚砜相比)均能逆转痛敏反应，提示混合制剂致敏的初级传入神经元同时表达TRPV1和ASICs。这些结果为NGF和GDNF之间的协同作用奠定了基础。
Key pointsNerve growth factor (NGF) and glial cell line‐derived neurotrophic factor (GDNF) are essential for neuronal development and survival in embryo. However, after birth they play pivotal roles in the generation of hyperalgesia in many painful conditions.Both factors are believed to act on different groups of primary afferents, but interaction between them has not yet been studied. Here we show a synergism between the two factors. Intramuscular injection of a mixture of both factors at a low concentration, each of which alone had no effect, induced a significant muscular mechanical hyperalgesia in rats.We show that synergism occurs in the primary afferent neurons and find that about 25% primary afferents innervating the muscle express both TrkA (NGF receptor) and GFRα1 (GDNF receptor).We show by pharmacological means that afferent neurons with TrkA and GFRα1 express both TRPV1 and ASICs.Our data establish a basis for synergism between NGF and GDNF.In some inflammatory conditions both nerve growth factor (NGF) and glial cell line‐derived neurotrophic factor (GDNF) are upregulated and play pivotal roles in inducing hyperalgesia. However, their interaction has not been studied. We examined whether and where interaction between both neurotrophic factors occurs in SD rats. Intramuscular injection to gastrocnemius muscle (GC) of a mixture of NGF (0.1 µm) and GDNF (0.008 µm), which alone had no effect, induced a significant mechanical hyperalgesia (F(6,30)= 13.62,P= 0.0001), demonstrating synergism between the two factors. Phosphorylated extracellular signal‐regulated kinase (pERK) immunoreactivity in dorsal root ganglia (DRGs) induced by compression of GC increased after injection of the mixture (P= 0.028, compared with PBS); thus the interaction of NGF and GDNF could occur at the primary afferent level. Anin situhybridization study (n= 4) demonstrated that 23.7–29.2% of GC‐innervating DRG neurons coexpressed TrkA (NGF receptor) and GFRα1 (GDNF receptor). The cell size of the coexpressing GC DRG neurons showed no skewing towards the small size range but was distributed widely from the small to the large size ranges. Therefore, some of the coexpressing neurons with thin axons are thought to contribute to this mechanical hyperalgesia. The hyperalgesia was reversed by both amiloride (F(1,13)= 5.056,P= 0.0425, compared with PBS) and capsazepine (F(1,10)= 8.402,P= 0.0159, compared with DMSO), suggesting that the primary afferents sensitized by the mixture express both TRPV1 and ASICs. These results showed a basis of synergism between NGF and GDNF.