Role of Growth Factors in Persistent Pain

神经营养因子家族(NGF、NT-3、BDNF和NT-4)和GDNF家族，包括青蒿素和 神经突触蛋白已被证明对感觉神经元的发育至关重要。伤害性感受器已经被证明 尤其依赖NGF和GDNF。我们实验室的初步研究表明，青蒿素 和神经生长因子一样，神经突触蛋白也会影响伤害性感受器的存活和反应。这些观察结果让我们 提出NGF是伤害性感受器胚胎发育所必需的一般假设，但在伤害感受器胚胎发育后期 发育、NGF和GDNF家族共同调节伤害性感受器的可塑性和表型。目标是 这项提议的目的是检验三种关于青蒿素和神经突蛋白作用的假说。 SA1验证了神经肽调节伤害性感受器综合表型(CP)的假说。 具体地说，我们预测神经肽在IB4阳性的发展和分化中起重要作用。 多模式伤害性感受器，它直接影响这些神经元的热反应。 SA2验证了与NGF一样，神经图灵和青蒿素可以调节出生后感觉神经元的假设 表型和可塑性。我们有初步数据表明神经肽和青蒿素可能更有效。 与NGF相比，NGF对初级传入细胞具有更强的敏化作用。这是一个令人兴奋的结果，因为这是这个家庭第一次 生长因子，像NGF一样，是在感觉神经元的靶标中产生的，已经被证明可以改变感觉 神经元反应特性。 SA3验证了一种假设，即炎症引起的初级传入改变依赖于 青蒿素和神经图灵。NGF被认为在炎性疼痛中起着重要作用，因为它 敏化初级传入神经的能力，因为它在炎症过程中增加。我们的初步数据 结果表明，炎症诱导后24小时，青蒿素基因的表达水平是神经生长因子基因表达的10倍以上。 在SA3中，我们将扩展这些研究，并尝试使用针对青蒿素的siRNA来抑制炎症性疼痛， 神经突触蛋白和神经生长因子及其受体。

The neurotrophin family (NGF, NT-3, BDNF and NT-4) and the GDNF family that includes, artemin and neurturin have been shown to be crucial for sensory neuron development. Nociceptors have been shown to be particularly dependent on NGF and GDNF. Preliminary studies from our laboratories show that artemin and neurturin can, like NGF, affect nociceptor survival and responsiveness. These observations have led us to propose the general hypothesis that NGF is required for nociceptor embryogenesis but that during late development, NGF and the GDNF family combine to regulate nociceptor plasticity and phenotype. The goal of this proposal is to test three hypotheses addressing the roles of artemin and neurturin. SA1 tests the hypothesis that neurturin modulates the comprehensive phenotype (CP) of nociceptors. Specificially, we predict that neurturin is important for the development and differentiation of IB4-positive polymodal nociceptors and that it directly affects the heat responsiveness of these neurons. SA2 tests the hypothesis that like NGF, neurturin and artemin can regulate postnatal sensory neuron phenotype and plasticity. We have preliminary data that neurturin and artemin may be even more potent than NGF for sensitizing primary afferents. This is an exciting result as this is the first time that this family of growth factors, that like NGF is made in the targets of sensory neurons, has been shown to alter sensory neuron response properties. SA3 tests the hypothesis that the alterations of primary afferents induced by inflammation are dependent on artemin and neurturin. NGF has been thought to play an important role in inflammatory pain because of its ability to sensitize primary afferents and because it increases during inflammation. Our preliminary data shows that artemin mRNA increases 10-fold more than NGF mRNA 24 hrs after induction of inflammation. In SA3 we will extend these studies and attempt to block inflammatory pain using siRNAs for artemin, neurturin and NGF and their receptors.