Spinal Plasticity In Diabetic Neuropathic Pain

描述(申请人提供)：糖尿病神经病变是困扰糖尿病患者的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止痛药得到充分缓解，因此它代表着一个重要的未得到满足的临床需求。本研究的主要目的是研究糖尿病神经病理性疼痛中脊髓M受体的变化和M受体的镇痛机制。有初步证据表明，糖尿病患者脊髓中M受体表达上调，这可能是糖尿病神经病理性疼痛增强M受体镇痛作用的原因。此外，初步研究表明，抑制谷氨酸能突触传入背角神经元是脊髓注射胆碱能药物治疗糖尿病神经病理性疼痛的重要机制。将使用糖尿病动物模型检验下列假说：1)糖尿病患者脊髓背角M受体上调；M受体M2/M4增加在脊髓注射胆碱能药物增强糖尿病的镇痛作用中发挥重要作用；2)M受体激活导致糖尿病患者脊髓初级传入终末释放更显著的谷氨酸；M受体激动剂诱导GABA释放，从而激活突触前GABAB受体以抑制谷氨酸释放到糖尿病脊髓板层II神经元；3)脊髓注射胆碱能神经元的抑制作用和伤害性感受在更大程度上是由脊髓GABAB受体介导的。将使用G蛋白偶联受体的定量测量，脊髓背角神经元的单位记录，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，以及伤害性感觉的行为评估。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改变的机制很重要。这一新信息还将为糖尿病神经病理性疼痛患者改进治疗方法的开发提供理论基础。

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.