Jankowski Michael P, Baumbauer Kyle M, Wang Ting, Albers Kathryn M, Davis Brian M, Koerber H Richard
Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania
J Neurophysiol. 2017 Mar 1;117(3):1258-1265. doi: 10.1152/jn.00731.2016. Epub 2016 Dec 28.
Neurotrophic factors play an important role in the regulation of functional properties of sensory neurons under normal and pathological conditions. The GDNF family member neurturin is one such factor that has been linked to modulating responsiveness to peripheral stimuli. Neurturin binds to the GFRα2 receptor, a receptor found primarily in isolectin B-expressing polymodal cutaneous nociceptors. Previous work has shown that knockout of GFRα2 alters heat, but not mechanical, responses in dissociated sensory neurons and reduces pain-related behaviors during the second phase of the formalin test. Research has also shown that overexpression of neurturin in basal keratinocytes increases behavioral responsiveness to mechanical stimulation and innocuous cooling of the skin without affecting noxious heat responses. Here we directly examined the impact of neurturin overexpression on cutaneous afferent function. We compared physiological responses of individual sensory neurons to mechanical and thermal stimulation of the skin, using an ex vivo skin-nerve-dorsal root ganglion-spinal cord preparation produced from neurturin-overexpressing (NRTN/OE) mice and wild-type littermate controls. We found that neurturin overexpression increases responsiveness to innocuous mechanical stimuli in A-fiber nociceptors, alters thermal responses in the polymodal subpopulation of C-fiber sensory neurons, and changes the relative numbers of mechanically sensitive but thermally insensitive C-fiber afferents. These results demonstrate the potential roles of different functional groups of sensory neurons in the behavioral changes observed in mice overexpressing cutaneous neurturin and highlight the importance of neurturin in regulating cutaneous afferent response properties. GDNF family neurotrophic factors regulate the development and function of primary sensory neurons. Of these, neurturin has been shown to modulate mechanical and cooling sensitivity behaviorally. Here we show that overexpression of neurturin in basal keratinocytes regulates mechanical responsiveness in A-fiber primary sensory neurons while increasing the overall numbers of cold-sensing units. Results demonstrate a crucial role for cutaneous neurturin in modulating responsiveness to peripheral stimuli at the level of the primary afferent.
神经营养因子在正常和病理条件下对感觉神经元功能特性的调节中起着重要作用。胶质细胞源性神经营养因子（GDNF）家族成员神经生长因子（Neurturin）就是这样一种与调节对外周刺激的反应性有关的因子。神经生长因子与GFRα2受体结合，该受体主要存在于表达异凝集素B的多模式皮肤伤害感受器中。先前的研究表明，敲除GFRα2会改变离体感觉神经元的热反应，但不会改变机械反应，并会减少福尔马林试验第二阶段的疼痛相关行为。研究还表明，基础角质形成细胞中神经生长因子的过表达会增加对机械刺激和皮肤无害冷却的行为反应性，而不会影响有害热反应。在这里，我们直接研究了神经生长因子过表达对皮肤传入功能的影响。我们使用从过表达神经生长因子（NRTN/OE）的小鼠和野生型同窝对照产生的离体皮肤-神经-背根神经节-脊髓标本，比较了单个感觉神经元对皮肤机械和热刺激的生理反应。我们发现，神经生长因子过表达会增加A纤维伤害感受器对无害机械刺激的反应性，改变C纤维感觉神经元多模式亚群中的热反应，并改变机械敏感但热不敏感的C纤维传入纤维的相对数量。这些结果证明了感觉神经元不同功能组在过表达皮肤神经生长因子的小鼠中观察到的行为变化中的潜在作用，并突出了神经生长因子在调节皮肤传入反应特性中的重要性。GDNF家族神经营养因子调节初级感觉神经元的发育和功能。其中，神经生长因子已被证明在行为上调节机械和冷却敏感性。在这里，我们表明基础角质形成细胞中神经生长因子的过表达调节A纤维初级感觉神经元的机械反应性，同时增加冷感受单位的总数。结果证明了皮肤神经生长因子在初级传入水平调节对外周刺激反应性中的关键作用。
