Spinal Plasticity In Diabetic Neuropathic Pain

描述（由申请人提供）：糖尿病神经病变是困扰糖尿病患者的最重要并发症之一。由于糖尿病神经病变引起的慢性疼痛通常不能通过传统镇痛药充分缓解，因此它代表了重要的未满足的临床需求。该提案的主要目标是研究糖尿病神经病理性疼痛中脊髓毒蕈碱受体的变化和毒蕈碱镇痛机制。初步证据表明，在脊髓中的毒蕈碱受体上调糖尿病，这可能是增强的毒蕈碱镇痛在糖尿病神经病理性疼痛。此外，初步研究表明，抑制背角神经元的突触输入是脊髓给药的胆碱能药物在糖尿病神经病理性疼痛的重要镇痛机制。将使用糖尿病动物模型来检验以下假设：1）脊髓背角中的毒蕈碱受体在糖尿病中上调;脊髓毒蕈碱M2/M4受体的增加在糖尿病中脊髓施用的胆碱能药物的增强的镇痛作用中起主要作用; 2）在糖尿病中，毒蕈碱受体的激活引起初级传入终末的脊髓谷氨酸释放的更显著的减少;毒蕈碱受体激动剂引起GABA释放，其激活突触前GABAB受体以抑制谷氨酸释放到糖尿病中的脊髓板层II神经元上;和3）脊髓施用的胆碱能剂对脊髓丘脑束神经元和伤害感受的抑制作用在更大程度上由糖尿病中的脊髓GABAB受体介导。将使用G蛋白偶联受体的定量测量、脊髓背角神经元的单单位记录、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受的行为评估。这些综合研究对于我们理解糖尿病神经病理性疼痛中脊髓药理学改变的机制是重要的。这一新的信息也将为糖尿病神经性疼痛患者的改进治疗提供理论基础。

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.