PERIPHERAL GLUTAMATE RECEPTORS IN NEUROPATHIC PAIN

谷氨酸是中枢神经系统的重要递质， 对谷氨酸的功能及其作用的研究很少， 皮肤中的受体。 然而，最近的研究表明， 谷氨酸对离体大鼠尾部皮肤的镇痛作用 脊髓前根反射，表明谷氨酸可能起作用 作为一种神经递质在周围神经末梢的水平。 另一系列证据支持外周血管的重要作用 谷氨酸在伤害感受中的作用是我们初步的免疫组织化学数据， AMPA、红藻氨酸和NMDA受体在大鼠无髓轴突中的定位 光滑的皮肤 本项目的长期目标是阐明 外周谷氨酸受体在伤害性传递中的作用。 一旦在正常大鼠中确定了这一点， 谷氨酸及其受体对感觉异常的表征， 将研究疼痛性周围神经病变的动物模型。 初步数据表明，在这种病理生理状态下， 外周谷氨酸受体的激活增强神经性疼痛， 相反，阻断这些受体会减少疼痛行为。 所以我们 数据有力地表明，皮肤中的谷氨酸受体激活是一种 迄今为止尚未认识到重要外围机制， 导致感觉异常和疼痛 具体目标是 本研究的重点是1）确定谷氨酸受体的位置 亚型对皮肤中的神经元素; 2）阐明的作用， 外周谷氨酸受体在伤害性传递中的作用 和神经病大鼠; 3）确定初级传入活动是否 导致皮肤中谷氨酸盐含量增加：4）测定 外周轴突的致敏是否是一种潜在的机制 现象和5）确定交感传出神经在 谷氨酸诱发的伤害性感受 深入了解谷氨酸的作用 受体在皮肤的幼稚和神经病大鼠有许多临床 后果 病理性疼痛状态的治疗是可以想象的 涉及谷氨酸拮抗剂作为局部软膏或局部 注射剂 利用这种外周谷氨酸受体机制， 导致疼痛病症的改善的临床治疗。

Glutamate is an important transmitter in the central nervous system but there has been minimal investigation of the function of glutamate and its receptors in the skin. Recently, however, it has been demonstrated that application of glutamate to isolated rat tail skin elicits nociceptive reflexes in spinal cord ventral roots, indicating that glutamate may serve as a neurotransmitter at the level of the peripheral nerve terminal. Another line of evidence supporting an important role for peripheral glutamate in nociception is our preliminary immunohistochemical data, localizing AMPA, kainate and NMDA receptors in unmyelinated axons in rat glabrous skin. The long-term goal of this project is to elucidate the role of the peripheral glutamate receptors in nociceptive transmission. Once this is defined in normal rats, the contributions of peripheral glutamate and its receptors to sensory abnormalities characterizing an animal model of painful peripheral neuropathy will be investigated. Preliminary data indicate that in this pathophysiological state, activation of peripheral glutamate receptors enhances neuropathic pain, in contrast, blocking these receptors decreases pain behaviors. Thus, our data strongly suggest that glutamate receptor activation in the skin is an important peripheral mechanism which has heretofore been unrecognized as a contributor to sensory abnormalities and pain. The specific aims in this proposal focus on 1) identifying the location of glutamate receptor subtypes on neural elements in the skin; 2) elucidating the role of peripheral glutamate receptors in nociceptive transmission in both normal and neuropathic rats; 3) determining whether primary afferent activity results in an increase in glutamate content in the skin: 4) determining whether sensitization of peripheral axons is a mechanism underlying this phenomenon and 5) determining the role of the sympathetic efferents in glutamate-evoked nociception. Insight into the role of glutamate receptors in the skin of naive and neuropathic rats has many clinical ramifications. Therapy for pathological pain states could conceivable involve glutamate antagonists applied as topical ointments or local injections. Exploiting this peripheral glutamate receptor mechanism may result in improved clinical treatment of pain disorders.