Modulation of Spinal Cord LTP by Kappa Opioids

描述（由申请人提供）：在实验动物和人类中，强烈的伤害性刺激可以对后来的有害刺激产生中枢敏化。长期增强（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。

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.