PERIPHERAL GLUTAMATE RECEPTORS IN NEUROPATHIC PAIN

谷氨酸是中枢神经系统的重要递质，但 关于谷氨酸和谷氨酸的功能的研究很少 皮肤中的受体。然而，最近已经证明， 谷氨酸在大鼠离体尾皮肤的应用引起伤害性反应 脊髓腹根的反射，表明谷氨酸可能起作用 作为周围神经末梢水平的神经递质。 支持外围设备发挥重要作用的另一条证据 伤害性感受中的谷氨酸是我们初步的免疫组织化学数据， 大鼠无髓轴突内AMPA、海人藻酸和NMDA受体的定位 无毛的皮肤。这个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，外周血细胞的作用 谷氨酸及其受体对感官异常的特征 将研究痛性周围神经病的动物模型。 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了神经病理性疼痛 相比之下，阻断这些受体可以减少疼痛行为。因此，我们的 数据有力地表明，皮肤中谷氨酸受体的激活是一种 重要的外围机制，到目前为止还没有被认识到 导致感觉异常和疼痛的因素。其中的具体目标 这项建议的重点是1)确定谷氨酸受体的位置 皮肤中神经元素的亚型；2)阐明 外周谷氨酸受体在伤害性传递中的作用 和神经病理性大鼠；3)测定初级传入活动 导致皮肤中谷氨酸含量的增加：4)确定 外周轴突的敏感化是否是其背后的机制 5)确定交感神经传出在脑内的作用 谷氨酸引起的伤害性感受。对谷氨酸作用的洞察 幼稚和神经病大鼠皮肤中的受体有许多临床意义 后果。病理性疼痛状态的治疗是可能的 涉及将谷氨酸拮抗剂用作局部软膏或局部应用 打针。利用这种外周谷氨酸受体机制可能 结果改善了疼痛障碍的临床治疗。

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.