The Prefrontal Cortex in Neuropathic pain

疼痛是导致人们寻求医疗保健的最常见动机。当它变成慢性时，疼痛可以 会产生几种长期影响，如抑郁、失眠、免疫功能低下、 移动性和其他长期有害后果，其中几个提示皮质参与 与较高认知功能有关的区域。尽管在过去的15年里先进的动物模型 彻底改变了我们对慢性疼痛机制的理解，在这些模型中获得的知识 主要集中在涉及传入输入、脊髓突起和下行的机制 调制。人们对脊椎上的机制知之甚少，更不知道疼痛和疼痛的相互作用 皮质突起。最近对慢性背痛患者的人脑成像研究表明 前额叶皮质过度活动，即使在没有伤害性外周输入的情况下。其他研究表明 慢性疼痛患者的决策任务障碍和动物模型显示 可逆地阻断内侧前额叶皮质的神经元活动可减少神经病理性疼痛。动物 炎性疼痛的研究显示了谷氨酸能突触传递的功能后果 前额叶皮质。所有这些观察表明，可能存在功能和形态上的变化 在患有神经病理性疼痛的动物的前额叶皮质中。我们将在SNI大鼠身上研究这一假说， 高度可重复性的神经病理性疼痛模型。膜片钳记录及形态分析 生物细胞蛋白填充的神经元将被用于比较锥体的功能和形态特征 SNI和假手术动物的内侧前额叶皮质神经元。我们将比较 SNI和假手术组动物的树突数目和长度以及树突棘密度。 将进行免疫组织化学分析，以研究分子标志物的表达 神经元重组。其内在电生理特性及药理特性 谷氨酸能突触传递也将被研究。有核补丁记录和快速解决方案 将使用Exchange对谷氨酸受体的功能特性进行详细研究 在对照组和SNI大鼠的mPFC锥体神经元中均有表达。我们的初步数据显示，与 与假手术组相比，SNI大鼠的mPFC神经元表达更高水平的c-Fos，具有更大的 树突树、树突棘密度增加和谷氨酸受体的分子组成不同。 有趣的是，这些变化中有几个与受伤爪子的痛阈值有关。这些 观察结果支持我们的假设，即神经病理性疼痛导致mPFC的功能重组。 我们实验的成功完成可能代表着细胞研究的一次飞跃 神经病理性疼痛的机制和新的研究领域。

Pain is the most common motive leading people to seek health care. When it becomes chronic, pain can produce several long term effects such as depression, loss of sleep, depressed immune function, decreased mobility, and other long-term deleterious consequences, several of which suggest the involvement of cortical areas implicated in higher cognitive functions. Although animal models advanced over the last 15 years have revolutionized our understanding of chronic pain mechanisms, the knowledge garnered in these models has concentrated primarily on mechanisms involving afferent inputs, spinal cord processes, and descending modulation. Little is known about supraspinal mechanisms, even less so about the interaction of pain and cortical processes. Recent human brain imaging studies in chronic back pain patients indicate medial prefrontal cortical hyperactivity, even in absence of nociceptive peripheral inputs. Other studies show impairment of decision making tasks in patients suffering of chronic pain and animal models show that blocking neuronal activity in the medial prefrontal cortex reversibly decreases neuropathic pain. Animal studies on inflammatory pain show functional consequences on glutamatergic synaptic transmission in the prefrontal cortex. All these observations suggest that functional and morphological changes may be present in the prefrontal cortex of animals with neuropathic pain. We will investigate this hypothesis in SNI rats, a highly reproducible model of neuropathic pain. Patch clamp recordings and morphological analysis of biocytin filled neurons will be performed to compare the functional and morphological properties of pyramidal neurons of the medial prefrontal cortex (mPFC) of SNI and sham-operated animals. We will compare the number and length of the dendrites and the dendritic spine density in SNI and sham-operated animals. Immunohistochemical analysis will be performed to investigate the expression of molecular markers of neuronal reorganization. Intrinsic electrophysiological properties as well as the pharmacological properties of glutamatergic synaptic transmission will also be investigated. Nucleated patch recordings and fast solution exchange will be used to perform a detailed study of the functional properties of the glutamate receptors expressed in mPFC pyramidal neurons of control and SNI rats. Our preliminary data show that, compared to sham-operated counterparts, mPFC neurons from SNI rats expressed higher levels of c-Fos, have larger dendritic trees, increased dendritic spine density and different molecular composition of glutamate receptors. Interestingly, several of these changes are correlated with the pain threshold in the injured paw. These observations support our hypothesis that neuropathic pain induces functional reorganization of the mPFC. Successful completion of our experiments could represent a leap forward in the study of the cellular mechanisms of neuropathic pain and open new fields of investigation.