Central glia/cytokines and descending facilitation in orofacial neuropathic pain

描述（由申请人提供）：临床口面部疼痛综合征通常被认为与创伤或牙科手术导致的三叉神经损伤有关，并且对治疗提出了最困难的挑战。三叉神经痛的发生频率高于脊髓水平，但大多数关于神经痛的动物研究描述的数据来自脊髓神经损伤的动物模型。因此，为了阐明三叉神经性疼痛的机制，必须建立专门针对三叉神经系统的动物模型。有证据表明神经性疼痛的维持依赖于来自吻侧腹内侧髓质（RVM）的下行促进，RVM是下行疼痛调节的关键结构。最近的研究表明，激活的神经胶质细胞和释放的促炎细胞因子与神经损伤后的脊髓致敏密切相关。然而，RVM中胶质-神经元相互作用对神经性疼痛发展的潜在贡献尚未得到研究。我们建议用一种新的损伤测量方法来改进大鼠眶下神经（CCI-ION）慢性收缩损伤模型，并研究三叉神经性疼痛下行易化的新机制，重点研究RVM中胶质-神经元的相互作用。我们的主要假设是：1)神经损伤通过激活神经胶质和谷氨酸受体及其相关信号通路诱导RVM神经元的可塑性；2)神经胶质的激活和细胞因子的释放通过与神经谷氨酸受体的相互作用影响或促进神经元的可塑性，并在神经性疼痛的发生中发挥关键作用。Aim 1将建立一种可靠的方法来测量CCI-ION模型中的机械性痛觉过敏和异位性疼痛，并验证神经损伤后RVM中胶质细胞被激活和促炎细胞因子上调的假设。目的2将验证CCI-ION后这些细胞因子受体在RVM神经元中表达并在RVM中上调的假设。目的3将验证RVM中神经胶质功能的抑制和细胞因子作用的阻断可减轻CCI-ION相关的异位性痛的假设。目的4将验证神经胶质激活和伴随的细胞因子释放通过与神经元谷氨酸受体的相互作用参与RVM神经可塑性的假设，并在神经性疼痛的下行促进中发挥关键作用。这些研究将促进我们对口面部神经性疼痛机制的理解，并促进新的治疗方法的设计。

DESCRIPTION (provided by applicant): The clinical orofacial pain syndromes are believed to be frequently related to trigeminal nerve damage as a result of trauma or dental surgery and offer a most difficult challenge to therapy. Trigeminal neuropathic pain occurs more frequently than that at spinal levels, but most animal studies on neuropathic pain describe data from animal models of spinal nerve injuries. Thus, in order to clarify the mechanisms underlying trigeminal neuropathic pain, animal models have to be created specifically for the trigeminal system. Evidence has emerged that the maintenance of neuropathic pain depends on descending facilitation from the rostral ventromedial medulla (RVM), a pivotal structure in descending pain modulation. Recent studies suggest that activated glial cells and released proinflammatory cytokines are intimately involved in spinal sensitization after nerve injury. However, a potential contribution of glial-neuronal interactions in the RVM to the development of neuropathic pain has not been studied. We propose to modify a rat model of chronic constriction injury of the infraorbital nerve (CCI-ION) with a new nocifensive measurement and study novel mechanisms underlying descending facilitation of trigeminal neuropathic pain with an emphasis on glial-neuronal interactions in the RVM. Our major hypotheses are that 1) nerve injury induces neuronal plasticity in the RVM through activation of glial and glutamate receptors and related signaling pathways and 2) glial activation and cytokine release affect or facilitate neuronal plasticity through interactions with neuronal glutamate receptors and play a critical role in the development of neuropathic pain. Aim 1 will set up a reliable method to measure mechanical hyperalgesia and allodynia in the CCI-ION model and to test the hypothesis that glial cells are activated and proinflammatory cytokines are upregulated in the RVM after nerve injury. Aim 2 will test the hypothesis that the receptors of these cytokines are expressed in RVM neurons and upregulated in the RVM after CCI-ION. Aim 3 will test the hypothesis that the inhibition of glial function and blockade of cytokine action in the RVM attenuate allodynia associated with CCI-ION. Aim 4 will test the hypothesis that glial activation and concomitant cytokine release are involved in neural plasticity in the RVM through interactions with neuronal glutamate receptors, and play a critical role in descending facilitation of neuropathic pain. The studies will advance our understanding of the mechanisms of orofacial neuropathic pain and facilitate the design of new therapeutic approaches.