Modulation of Spinal Cord LTP by Kappa Opioids

Kappa 阿片类药物对脊髓 LTP 的调节

• 批准号: 6576440
• 负责人: GREGORY W TERMAN
• 金额: $ 31.53万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6576440
• 关键词: NMDA receptors; behavior test; chemosensitizing agent; dynorphins; electrophysiology; endogenous opioid; fluorescent dye /probe; inhibitor /antagonist; laboratory rat; long term potentiation; microelectrodes; neural transmission; nociceptors; opiate alkaloid; pain; spinal cord; stereotaxic techniques; voltage /patch clamp

DESCRIPTION (provided by applicant): Intense nociceptive stimuli can produce a central sensitization to later noxious stimulation in both laboratory animals and man. Long term potentiation (LTP), the best-studied cellular model of neuroplasticity within the CNS, involves a seemingly permanent increase in neuronal excitation following repeated activation of afferent input to that neuron. We have recently developed a model of LTP in the spinal cord slice preparation and begun to investigate its pharmacological and physiological characteristics using visualized whole cell voltage clamp recordings. Mu opiates inhibit induction of spinal LTP. Both exogenous and endogenous kappa opiates also inhibit LTP but act primarily by inhibiting maintenance mechanisms. In this proposal we plan to expand our studies of LTP in the spinal cord slice by: 1) using imaging techniques to specifically target dorsal horn nociceptors (i.e., selecting back-filled spinothalamic cells with three dimensional morphologies characteristic of nociceptors) for further experiments on kappa modulation of spinal LTP. 2) examining animals previously sensitized to noxious stimuli by inflammation (with resultant long-term anatomical and physiological changes in spinal pain circuitry) to correlate behavioral evidence of sensitization with electrophysiological evidence of spinal LTP including sensitivity to kappa opioids. 3) studying the dose related effects of dynorphin in modulating Lamina I neurotransmission and LTP, including differentiation of its kappa opiate and NMDA receptor activities. Such investigations of LTP in the spinal cord will lead to a better understanding of CNS neuroplasticity, in general, and nociceptive sensitization, in particular, and may ultimately lead to better pharmacological means of managing or preventing certain pain states.

描述（由申请人提供）：强烈的伤害性刺激可以对实验动物和人类产生对随后的伤害性刺激的中枢敏化。长时程增强（LTP）是中枢神经系统内神经可塑性研究最充分的细胞模型，涉及神经元传入输入重复激活后看似永久性的神经元兴奋增加。我们最近在脊髓切片制备中开发了 LTP 模型，并开始使用可视化全细胞电压钳记录研究其药理学和生理学特性。 Mu 阿片类药物抑制脊髓 LTP 的诱导。外源性和内源性卡帕阿片剂也抑制 LTP，但主要通过抑制维持机制发挥作用。 在本提案中，我们计划通过以下方式扩展我们对脊髓切片中 LTP 的研究：1）使用成像技术专门针对背角伤害感受器（即选择具有伤害感受器三维形态特征的回填脊髓丘脑细胞），以进一步进行脊髓 LTP 的 kappa 调制实验。 2) 检查先前因炎症而对有害刺激敏感的动物（导致脊髓疼痛回路的长期解剖和生理变化），将致敏的行为证据与脊髓 LTP 的电生理学证据（包括对卡帕阿片类药物的敏感性）关联起来。 3) 研究强啡肽在调节 Lamina I 神经传递和 LTP 中的剂量相关效应，包括其 kappa 阿片剂和 NMDA 受体活性的分化。 对脊髓中 LTP 的此类研究将有助于更好地了解中枢神经系统神经可塑性，特别是伤害感受敏化，并可能最终导致更好的药理学手段来管理或预防某些疼痛状态。