PDF(Pubmed)
Abstract：
OBJECTIVE: Following a mild traumatic brain injury (mTBI), the most prevalent and profoundly debilitating occurrence is the emergence of an acute and persistent post-traumatic headache (PTH), for which there are presently no approved treatments. A crucial gap in knowledge exists regarding the consequences of an mTBI, which could serve as a foundation for the development of therapeutic approaches. The activation of trigeminal sensory nerve terminals that innervate the calvarial periosteum (CP)-a densely innervated tissue layer covering the calvarial skull-has been implicated in both migraines and PTHs. We have previously shown that trigeminal oxytocin receptors (OTRs) may provide a therapeutic target for PTHs. This study examined the expression of oxytocin receptors on trigeminal nerves innervating the periosteum and whether these receptors might serve as a therapeutic target for PTHs using a direct application of oxytocin to the periosteum in a rodent model of PTH.
METHODS: We used retrograde tracing and immunohistochemistry to determine if trigeminal ganglion (TG) neurons innervating the periosteum expressed OTRs and/or CGRPs. To model the impact of local inflammation that occurs following an mTBI, we applied chemical inflammatory mediators directly to the CP and assessed for changes in immediate-early gene expression as an indication of neuronal activation. We also determined whether mTBI would lead to expression changes to OTR levels. To determine whether these OTRs could be a viable therapeutic target, we assessed the impact of oxytocin injections into the CP in a mouse model of PTH-induced periorbital allodynia.
RESULTS: The results of these experiments demonstrate the following: (1) the cell bodies of CP afferents reside in the TG and express both OTRs and CGRPs; (2) inflammatory chemical stimulation of the periosteum leads to rapid activation of TG neurons (phospho-ERK (p-ERK) expression), (3) mTBI-induced inflammation increased OTR expression compared to the sham group; and (4) administration of oxytocin into the periosteum on day 2 and day 40 blocked cutaneous allodynia for up to one hour post-administration for both acute and persistence phases in the PTH model-an effect that was preventable by the administration of an OTR antagonist.
CONCLUSIONS: Taken together, our observations suggest that periosteal trigeminal afferents contribute to post-TBI craniofacial pain, and that periosteum tissue can be used as a potential local target for therapeutics such as oxytocin.
METHODS: We used retrograde tracing and immunohistochemistry to determine if trigeminal ganglion (TG) neurons innervating the periosteum expressed OTRs and/or CGRPs. To model the impact of local inflammation that occurs following an mTBI, we applied chemical inflammatory mediators directly to the CP and assessed for changes in immediate-early gene expression as an indication of neuronal activation. We also determined whether mTBI would lead to expression changes to OTR levels. To determine whether these OTRs could be a viable therapeutic target, we assessed the impact of oxytocin injections into the CP in a mouse model of PTH-induced periorbital allodynia.
RESULTS: The results of these experiments demonstrate the following: (1) the cell bodies of CP afferents reside in the TG and express both OTRs and CGRPs; (2) inflammatory chemical stimulation of the periosteum leads to rapid activation of TG neurons (phospho-ERK (p-ERK) expression), (3) mTBI-induced inflammation increased OTR expression compared to the sham group; and (4) administration of oxytocin into the periosteum on day 2 and day 40 blocked cutaneous allodynia for up to one hour post-administration for both acute and persistence phases in the PTH model-an effect that was preventable by the administration of an OTR antagonist.
CONCLUSIONS: Taken together, our observations suggest that periosteal trigeminal afferents contribute to post-TBI craniofacial pain, and that periosteum tissue can be used as a potential local target for therapeutics such as oxytocin.
摘要：
目标：轻度创伤性脑损伤（mTBI）后，最普遍和最严重的衰弱的发生是急性和持续的创伤后头痛（PTH）的出现，目前尚无批准的治疗方法。关于mTBI的后果，在知识上存在一个关键的差距，这可以作为治疗方法发展的基础。支配颅骨骨膜（CP）的三叉神经感觉神经末梢的激活-覆盖颅骨颅骨的密集神经支配组织层-与偏头痛和PTH有关。我们先前已经表明三叉神经催产素受体（OTR）可以为PTH提供治疗靶标。这项研究检查了催产素受体在支配骨膜的三叉神经上的表达，以及这些受体是否可以在PTH的啮齿动物模型中直接将催产素应用于骨膜作为PTH的治疗靶标。
方法：我们使用逆行追踪和免疫组织化学来确定支配骨膜的三叉神经节（TG）神经元是否表达OTR和/或CGRP。为了模拟mTBI后发生的局部炎症的影响，我们将化学炎症介质直接应用于CP,并评估了即刻早期基因表达的变化作为神经元激活的指标.我们还确定mTBI是否会导致OTR水平的表达变化。为了确定这些OTR是否可以成为可行的治疗靶标，在PTH诱导的眶周异常性疼痛小鼠模型中,我们评估了CP注射催产素的影响.
结果：这些实验的结果表明：（1）CP传入的细胞体位于TG中，并同时表达OTR和CGRP；（2）骨膜的炎症化学刺激导致TG神经元的快速激活（磷酸化-ERK（p-ERK）表达），(3)与假手术组相比,mTBI诱导的炎症增加了OTR表达;和(4)在第2天和第40天向骨膜中施用催产素阻断了PTH模型中急性期和持续期的皮肤异常性疼痛在施用后长达一小时-该作用可通过施用OTR拮抗剂来预防。
结论：综合来看，我们的观察表明，三叉神经骨膜传入有助于TBI后颅面疼痛，并且骨膜组织可以用作治疗如催产素的潜在局部靶标。
方法：我们使用逆行追踪和免疫组织化学来确定支配骨膜的三叉神经节（TG）神经元是否表达OTR和/或CGRP。为了模拟mTBI后发生的局部炎症的影响，我们将化学炎症介质直接应用于CP,并评估了即刻早期基因表达的变化作为神经元激活的指标.我们还确定mTBI是否会导致OTR水平的表达变化。为了确定这些OTR是否可以成为可行的治疗靶标，在PTH诱导的眶周异常性疼痛小鼠模型中,我们评估了CP注射催产素的影响.
结果：这些实验的结果表明：（1）CP传入的细胞体位于TG中，并同时表达OTR和CGRP；（2）骨膜的炎症化学刺激导致TG神经元的快速激活（磷酸化-ERK（p-ERK）表达），(3)与假手术组相比,mTBI诱导的炎症增加了OTR表达;和(4)在第2天和第40天向骨膜中施用催产素阻断了PTH模型中急性期和持续期的皮肤异常性疼痛在施用后长达一小时-该作用可通过施用OTR拮抗剂来预防。
结论：综合来看，我们的观察表明，三叉神经骨膜传入有助于TBI后颅面疼痛，并且骨膜组织可以用作治疗如催产素的潜在局部靶标。
