Modulation of Spinal Cord LTP by Kappa Opioids

超出所提供的空间。在实验动物和人类中，强烈的伤害性刺激可对后来的有害刺激产生中枢致敏。长时程增强（LTP）是研究得最好的中枢神经系统内神经可塑性的细胞模型，它涉及到神经元的传入输入反复激活后，神经元兴奋似乎永久增加。我们最近开发了脊髓切片制备中的LTP模型，并开始使用可视化的全细胞电压钳记录来研究其药理学和生理学特征。阿片类药物抑制脊髓LTP的诱导。外源性和内源性kappa阿片也抑制LTP，但主要通过抑制维持机制起作用。在本课题中，我们计划在脊髓片上扩展我们对LTP的研究：1)利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三维形态特征的脊髓丘脑背充细胞），进一步实验kappa对脊髓LTP的调节。2)检查先前因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和生理变化），将致敏的行为证据与脊髓LTP的电生理证据（包括对kappa阿片类药物的敏感性）联系起来。3)研究dynorphin调节I层神经传递和LTP的剂量相关效应，包括其阿片受体和NMDA受体活性的分化。这种对脊髓LTP的研究将有助于更好地理解中枢神经系统的可塑性，特别是伤害性致敏，并可能最终导致更好的药物手段来控制或预防某些疼痛状态。网站性能 ======================================== 节结束 ===========================================

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===========================================