Modulation of Spinal Cord LTP by Kappa Opioids

超出提供的空间。在实验动物和人类中，强烈的伤害性刺激都能对后来的伤害性刺激产生中枢敏化作用。长时程增强(LTP)是研究最多的中枢神经可塑性的细胞模型，它涉及到神经元传入信息的重复激活后，神经元兴奋性似乎是永久性的增加。我们最近在脊髓切片制备中建立了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和生理特性。MU阿片类药物抑制脊髓LTP的诱导。外源性和内源性kappa阿片剂也抑制LTP，但主要通过抑制维持机制发挥作用。在这项提议中，我们计划通过以下方式扩大我们对脊髓切片LTP的研究：1)使用成像技术特异性地靶向背角伤害性感受器(即选择具有伤害性感受器三维形态特征的背部填充的脊髓丘脑细胞)，以进一步实验脊髓LTP的kappa调节。2)检查以前因炎症而对伤害性刺激敏感的动物(由此导致的脊髓痛觉回路的长期解剖学和生理学变化)，以将敏化的行为证据与脊髓LTP的电生理证据相关联，包括对kappa阿片类药物的敏感性。3)研究强啡肽对纹状体I层神经递质和长时程增强的量效关系，包括其kappa阿片和NMDA受体活性的分化。对脊髓LTP的研究将有助于更好地了解中枢神经系统的可塑性，特别是伤害性敏感化，并最终可能导致更好的药物手段来管理或预防某些疼痛状态。表演网站========================================Section End===========================================

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