Central glia/cytokines and descending facilitation in orofacial neuropathic pain

描述(申请人提供)：临床口腔面部疼痛综合征被认为经常与三叉神经损伤有关，是创伤或牙科手术的结果，给治疗带来了最大的挑战。三叉神经病理性疼痛比脊髓水平更常见，但大多数关于神经病理性疼痛的动物研究都是从脊髓神经损伤的动物模型中获得数据。因此，为了阐明三叉神经病理性疼痛的机制，必须建立专门针对三叉神经系统的动物模型。有证据表明，神经病理性疼痛的维持依赖于延髓头端腹内侧(RVM)的下行促进，RVM是下行疼痛调制的关键结构。最近的研究表明，神经损伤后激活的神经胶质细胞和释放的促炎细胞因子与脊髓的敏化密切相关。然而，RVM中的神经胶质-神经元相互作用对神经病理性疼痛的发展的潜在贡献尚未被研究。我们建议用一种新的方法改进大鼠眶下神经慢性压迫损伤(CCI-ION)模型，并研究三叉神经病理性疼痛下行易化的新机制，重点是RVM中神经胶质-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相关的信号通路来诱导RVM的神经元可塑性；2)神经胶质的激活和细胞因子的释放通过与神经元谷氨酸受体的相互作用影响或促进神经元的可塑性，在神经病理性疼痛的发生中起关键作用。目的1建立一种可靠的方法来测量CCI离子模型中的机械性痛觉过敏和痛觉异常，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说。目的2验证CCI-离子后这些细胞因子受体在RVM神经元中表达并上调的假说。目的3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-离子引起的痛觉异常的假说。目的4验证胶质细胞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的神经可塑性的假说，并在神经病理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，并有助于设计新的治疗方法。

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.