Zhang Yi, Chen Yong, Liedtke Wolfgang, Wang Fan
Department of Neurobiology, Duke University Medical Center, Durham, NC, 27710, USA.
Department of Neurology, Center for Translational Neuroscience, Duke University Medical Center, Durham, NC, 27710, USA.
Mol Pain. 2015 Apr 10;11:18. doi: 10.1186/s12990-015-0017-2.
Mechanical and in particular tactile allodynia is a hallmark of chronic pain in which innocuous touch becomes painful. Previous cholera toxin B (CTB)-based neural tracing experiments and electrophysiology studies had suggested that aberrant axon sprouting from touch sensory afferents into pain-processing laminae after injury is a possible anatomical substrate underlying mechanical allodynia. This hypothesis was later challenged by experiments using intra-axonal labeling of A-fiber neurons, as well as single-neuron labeling of electrophysiologically identified sensory neurons. However, no studies have used genetically labeled neurons to examine this issue, and most studies were performed on spinal but not trigeminal sensory neurons which are the relevant neurons for orofacial pain, where allodynia oftentimes plays a dominant clinical role.
We recently discovered that parvalbumin::Cre (Pv::Cre) labels two types of Aβ touch neurons in trigeminal ganglion. Using a Pv::CreER driver and a Cre-dependent reporter mouse, we specifically labeled these Aβ trigeminal touch afferents by timed taxomifen injection prior to inflammation or infraorbital nerve injury (ION transection). We then examined the peripheral and central projections of labeled axons into the brainstem caudalis nucleus after injuries vs controls. We found no evidence for ectopic sprouting of Pv::CreER labeled trigeminal Aβ axons into the superficial trigeminal noci-receptive laminae. Furthermore, there was also no evidence for peripheral sprouting.
CreER-based labeling prior to injury precluded the issue of phenotypic changes of neurons after injury. Our results suggest that touch allodynia in chronic orofacial pain is unlikely caused by ectopic sprouting of Aβ trigeminal afferents.
机械性疼痛，尤其是触觉异常性疼痛是慢性疼痛的一个标志，即无害的触摸会变得疼痛。先前基于霍乱毒素B（CTB）的神经追踪实验和电生理学研究表明，损伤后触觉感觉传入神经的异常轴突发芽进入疼痛处理层是机械性异常性疼痛潜在的解剖学基础。该假说后来受到了使用A纤维神经元轴突内标记以及电生理鉴定的感觉神经元单神经元标记实验的挑战。然而，尚无研究使用基因标记的神经元来研究此问题，并且大多数研究是在脊髓而非三叉神经感觉神经元上进行的，而三叉神经感觉神经元是口面部疼痛相关的神经元，在口面部疼痛中异常性疼痛通常起主要临床作用。
我们最近发现，小白蛋白:: Cre（Pv:: Cre）标记三叉神经节中的两种Aβ触觉神经元。使用Pv:: CreER驱动程序和Cre依赖性报告基因小鼠，我们在炎症或眶下神经损伤（ION横断）之前通过定时注射他莫昔芬特异性标记了这些Aβ三叉神经触觉传入神经。然后，我们检查了损伤后与对照相比标记轴突向脑干尾侧核的外周和中枢投射。我们没有发现Pv:: CreER标记的三叉神经Aβ轴突异位发芽进入三叉神经浅表伤害感受层的证据。此外，也没有外周发芽的证据。
损伤前基于CreER的标记排除了损伤后神经元表型变化的问题。我们的结果表明，慢性口面部疼痛中的触觉异常性疼痛不太可能由Aβ三叉神经传入神经的异位发芽引起。
