Spinal Plasticity In Diabetic Neuropathic Pain

描述（申请人提供）：糖尿病神经病变是糖尿病患者最重要的并发症之一。由于糖尿病神经病变引起的慢性疼痛通常不能通过传统的镇痛药物充分缓解，这是一个重要的未满足的临床需求。本研究的主要目的是研究糖尿病神经性疼痛中脊髓毒蕈碱受体的变化和毒蕈碱镇痛的机制。初步证据表明，糖尿病患者脊髓中的毒蕈碱受体上调，这可能是糖尿病神经性疼痛中毒蕈碱镇痛增强的原因。此外，初步研究表明，抑制谷氨酸能突触对背角神经元的输入是脊髓给药胆碱能药物治疗糖尿病神经性疼痛的重要镇痛机制。以下假设将在糖尿病动物模型中得到验证：1)糖尿病患者脊髓背角的毒蕈碱受体上调；增加的脊髓毒蕈碱M2/M4受体在脊髓给药胆碱能药物对糖尿病的镇痛作用增强中起主要作用；2)激活毒蕈碱受体导致糖尿病患者原发性传入末梢脊髓谷氨酸释放更显著减少；毒蕈碱受体激动剂诱导GABA释放，激活突触前GABAB受体，抑制谷氨酸释放到糖尿病脊髓II层神经元；3)脊髓给药胆碱能药物对脊髓丘脑束神经元和痛觉的抑制作用在很大程度上是由糖尿病患者的脊髓GABAB受体介导的。G蛋白偶联受体的定量测量，脊髓背角神经元的单单元记录，脊髓切片中谷氨酸和gaba介导的突触后电流的全细胞电压钳记录，以及伤害感觉的行为评估将被使用。这些综合研究对于我们理解糖尿病神经性疼痛中脊髓改变的药理学机制非常重要。这一新信息也将为改善糖尿病神经性疼痛患者的治疗提供理论依据。

DESCRIPTION (provided by applicant): Diabetic neuropathy is one of the most important complications afflicting diabetic patients. Since chronic pain caused by diabetic neuropathy often is not adequately relieved by traditional analgesics, it represents an important unmet clinical need. The major objectives of this proposal are to study changes in spinal muscarinic receptors and mechanisms of muscarinic analgesia in diabetic neuropathic pain. Preliminary evidence is presented that muscarinic receptors in the spinal cord are up-regulated in diabetes, which may account for the enhanced muscarinic analgesia in diabetic neuropathic pain. Furthermore, the preliminary study suggests that inhibition of the glutamatergic synaptic input to dorsal horn neurons is an important analgesic mechanism of spinally administered cholinergic agents in diabetic neuropathic pain. The following hypotheses will be tested using animal models of diabetes: 1) Muscarinic receptors in the spinal cord dorsal horn are up-regulated in diabetes; Increased spinal muscarinic M2/M4 receptors play a major role in the enhanced analgesic action of spinally administered cholinergic agents in diabetes; 2) Activation of muscarinic receptors causes a more significant reduction in spinal glutamate release from primary afferent terminals in diabetes; Muscarinic receptor agonists elicit GABA release, which activates presynaptic GABAB receptors to inhibit glutamate release onto spinal lamina II neurons in diabetes; and 3) The inhibitory effects of spinally administered cholinergic agents on spinothalamic tract neurons and nociception are mediated, to a greater extent, by spinal GABAB receptors in diabetes. Quantitative measurements of G protein-coupled receptors, single-unit recordings of spinal dorsal horn neurons, whole-cell voltage-clamp recordings of glutamate- and GABA-mediated postsynaptic currents in spinal cord slices, and behavioral assessment of nociception will be used. These integrated studies are important for our understanding of the mechanisms of altered spinal cord pharmacology in diabetic neuropathic pain. This new information also will provide a rationale for development of improved therapies for patients with diabetic neuropathic pain.