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产生中心的敏感性，以使实验动物和人类的后来有害刺激产生中心敏感性。长期增强（LTP）是中枢神经系统内神经塑性的最佳细胞模型，涉及在反复激活该神经元的传入输入后，神经元激发似乎永久增加。我们最近在脊髓切片制备中开发了LTP模型，并开始使用可视化的全细胞电压夹记录来研究其药理和生理特征。 MU阿片类药物抑制脊柱LTP的诱导。外源性和内源性喀巴鸦片都可以抑制LTP，但主要是通过抑制维持机制的作用。 在此提案中，我们计划通过以下方面扩展对LTP的研究：1）使用成像技术专门针对背角伤害感受器（即，选择具有三维倍感摄影师特征的背面尖丘脑细胞），以在脊柱LTP的KAPPA调节上进行进一步实验。 2）检查先前通过炎症对有害刺激的动物（导致脊柱疼痛回路的长期解剖和生理变化），以将敏感性的行为证据与脊柱LTP的电生理证据相关联，包括对Kappa阿片类药物的敏感性。 3）研究末因在调节薄片I神经传递和LTP中的剂量相关作用，包括分化其Kappa鸦片和NMDA受体活性。 对脊髓中LTP的这种研究将导致对CNS神经可塑性的更好理解，尤其是伤害性敏感性，并最终可能导致更好地管理或预防某些疼痛状态的药理方法。