Modulation of Spinal Cord LTP by Kappa Opioids

超出所提供的空间。 在实验室动物和人类中，强烈的伤害性刺激可以产生对随后的伤害性刺激的中枢敏感化。长时程增强（LTP）是中枢神经系统内神经可塑性的最佳研究细胞模型，涉及在重复激活传入输入到该神经元之后神经元兴奋的看似永久的增加。我们最近开发了一个模型的LTP在脊髓切片制备，并开始研究其药理学和生理学特性，使用可视化的全细胞电压钳记录。Mu类阿片抑制脊髓LTP的诱导。外源性和内源性κ阿片类药物也抑制LTP，但主要通过抑制维持机制起作用。在这项提议中，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）使用成像技术特异性靶向背角伤害感受器（即，选择具有伤害感受器的三维形态特征的回填脊髓丘脑细胞）用于进一步的脊髓LTP的κ调节实验。2)检查先前通过炎症对有害刺激致敏的动物（导致脊髓疼痛回路的长期解剖学和生理学变化），以将致敏的行为证据与脊髓LTP的电生理学证据（包括对κ阿片样物质的敏感性）相关联。3)研究强啡肽在调节板层I神经传递和LTP中的剂量相关效应，包括其κ阿片和NMDA受体活性的分化。 脊髓中LTP的这种研究将导致更好地理解CNS神经可塑性，特别是伤害性敏化，并可能最终导致更好的管理或预防某些疼痛状态的药理学手段。性能现场=

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================