Mechanisms of Spinal Plasticity in Diabetic Neuropathic Pain

糖尿病神经病理性疼痛的脊柱可塑性机制

• 批准号: 7895931
• 负责人: Hui-Lin Pan
• 金额: $ 40.19万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895931
• 关键词: Absence of pain sensation; Affect; Afferent Neurons; Agonist; Analgesics; Animal Model; Arts; Cells; Cholinergic Receptors; Clinical; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Diabetic Neuralgia; Diabetic Neuropathies; Funding; Goals; Grant; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Interneurons; Intractable Pain; Knockout Mice; Measurement; Medical; Molecular; Muscarinic Acetylcholine Receptor; Muscarinics; Nerve; Neurons; Nociception; Pain; Pain management; Patients; Peripheral Nervous System Diseases; Play; Posterior Horn Cells; Proteins; Regulation; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Sensory; Slice; Small Interfering RNA; Spinal; Spinal Cord; Spinal Cord Plasticity; Spinal Ganglia; Synapses; Synaptic Transmission; System; Testing; Time; United States; Up-Regulation; acetylcholine transporter; cholinergic; chronic pain; diabetic; diabetic patient; dorsal horn; effective therapy; human CHRM4 protein; in vivo; interdisciplinary approach; neurotransmitter release; novel; painful neuropathy; patch clamp; postsynaptic; psychologic; social; spatiotemporal; transmission process

Diabetic neuropathy is one of the most important complications that afflict people with diabetes. Because chronic pain caused by diabetic neuropathy is not adequately relieved by existing analgesics, it represents an important unmet clinical need. The cholinergic system in the spinal cord is critically involved in the control of pain transmission. Although distinct M" M3 , and M. subtypes are involved in the regulation of excitatory and inhibitory neurotransmitter release to spinal dorsal horn neurons, little is known about how the function of these mAChR subtypes is altered in diabetic neuropathic pain. The major objectives of this proposal are to study the functional plasticity of spinal muscarinic acetylcholine receptor (mAChR) subtypes in the regulation of nociceptive transmission in painful neuropathy associated with type 1 diabetes. Our preliminary findings suggest that diabetic neuropathy affects primarily the M, and M. mAChR subtypes in the dorsal root ganglion and spinal cord. The specific aims of this project are to determine (1) the functional changes in mAChR subtypes in the spinal dorsal horn and dorsal root ganglion after induction of painful neuropathy in type 1 diabetes and (2) the roles of individual mAChR subtypes in the spinal cord in the control of nociception in diabetic neuropathic pain. Our central hypothesis is that diabetic neuropathy primarily upregulates M, and M. mAChRs on the primary sensory neurons and spinal dorsal horn neurons to inhibit nociceptive transmission. We will use a combination of multidisciplinary approaches including whole-cell patch-clamp recordings of postsynaptic currents in perfused spinal cord slices, real-time RT-PCR, and knockdown of spinal mAChR subtypes with small interfering RNA. These studies will provide substantial novel information about the mechanisms of plasticity in the spinal cholinergic system and mAChR subtypes in diabetic neuropathy. Findings from this project will provide a rationale for the development of new therapies for patients with intractable diabetic neuropathic pain.

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不能被现有的镇痛药充分缓解，这是一个重要的未满足的临床需求。脊髓胆碱能系统在疼痛传递的控制中起关键作用。虽然不同的M ' M3和M.亚型参与调节兴奋性和抑制性神经递质释放到脊髓背角神经元，但对它们的功能知之甚少