PRIMITIVE FOUNDATIONS OF NEUROPATHIC HYPERALGESIA

描述：总体目标是使用一个简单的无脊椎动物模型， 探索基本细胞机制创伤性神经病致敏 这可能是神经性痛觉过敏的重要底物， 是人类顽固性慢性疼痛的组成部分。 各种意见， 以及进化论的论点，表明一些基本的机制， 神经性致敏可能是广泛保守的。 识别 伤害感受器和其他神经元控制尾部撤回反射在 软体动物，Aaplasia californica，提供了一个特殊的机会来测试 特定细胞介质在诱导、表达和 终止涉及神经损伤的神经性致敏。 使用此 系统，涉及挤压损伤的神经性致敏模型， 尾部将被开发，允许直接测试的假设， 表达和诱导持续性行为和 持续数月的感官变化 测试将由 外周变化的贡献，包括传入神经的敏感化， 受损轴突的自发放电和背景神经调质 release. 持续性中枢变化的测试将检查过度兴奋 伤害感受器胞体，中间神经元和运动神经元，促进 中枢突触，去抑制，以及背景电和突触 活动 诱导机制的测试将检查快速， 活动依赖性信号，神经调质释放，长时程突触 增强和缓慢的轴浆信号。 一个关于 cAMP、钙离子和慢轴浆损伤信号的联合作用， 诱导持续性伤害感受器过度兴奋和增强 伤害感受器再生将在神经节的简化制备中进行测试 和神经，以及在细胞培养物中生长的分离的伤害感受器中。 其他 用于诱导的潜在细胞内和细胞外信号， 持续性伤害感受器过度兴奋的维持将开始 在单个细胞中筛选。

DESCRIPTION: The general objective is to use a simple invertebrate model of traumatic neuropathic sensitization to probe fundamental cellular mechanisms that may be important substrates for neuropathic hyperalgesia--a common component of intractable and chronic pain in humans. Various observations, as well as evolutionary arguments, suggest that some basic mechanisms of neuropathic sensitization are likely to be widely conserved. Identified nociceptors and other neurons controlling the tail withdrawal reflex in the mollusc, Aplysia californica, provide a special opportunity to test the roles of specific cellular mediators in the induction, expression, and termination of neuropathic sensitization involving nerve injury. Using this system, a model of neuropathic sensitization involving crush injury of the tail will be developed that allows direct tests of hypotheses about mechanisms underlying expression and induction of persistent behavioral and sensory alterations lasting for months. Tests will be made of the contributions of peripheral changes, including sensitization of afferents, spontaneous discharge of injured axons, and background neuromodulator release. Tests of persistent central changes will examine hyperexcitability of nociceptor somata, interneurons and motor neurons, facilitation of central synapses, disinhibition, and background electrical and synaptic activity. Tests of induction mechanisms will examine contributions of fast, activity-dependent signals, neuromodulator release, long-term synaptic potentiation, and slow axoplasmic signals. A general hypothesis about the combined role of cAMP, calcium ions and slow axoplasmic injury signals in the induction of persistent nociceptor hyperexcitability and enhancement of nociceptor regeneration will be tested in a reduced preparation of ganglia and nerves, and in isolated nociceptors growing in cell culture. Other potential intracellular and extracellular signals for induction and maintenance of persistent nociceptor hyperexcitability will begin to be screened in individual cells.