MODULATION OF SPINAL CORD NEUROPLASTICITY BY OPIOIDS

阿片类药物对脊髓神经可塑性的调节

• 批准号: 2700800
• 负责人: GREGORY W TERMAN
• 金额: $ 15.17万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2700800
• 关键词: Animalia; NMDA receptors; afferent nerve; gene induction /repression; long term potentiation; neural plasticity; neural transmission; neurochemistry; neuropharmacology; opiate alkaloid; opioid receptor; pain; spinal cord; synapses; voltage /patch clamp

APPLICANT'S ABSTRACT: This application is a request for a Scientist Development Award. This award is sought to enable my full time research on the modulatory effects of opiates on spinal cord neurotransmission and synaptic plasticity. These new research experiences under the tutelage of my preceptor and additional consultants will equip me technically and practically to move forward quickly to become an independent researcher. Long term potentiation (LTP), the best studied model, to date, of synaptic plasticity within the CNS, involves a seemingly permanent increase in neuronal excitation following repeated activation of afferent input to that neuron and is thought to be the cellular basis of learning. Recent clinical and behavioral evidence has accumulated suggesting that much the same activity- dependent synaptic changes can take place in neural systems involved in pain perception. Intense painful stimuli can produce a central sensitization to further noxious stimulation in both laboratory animals and man. Behavioral pharmacologic studies of this sensitization suggest numerous similarities to the neurochemistry of LTP, including its reliance on activation of the NMDA class of glutamate receptors and its modulation by certain opiates. The studies proposed here involve the utilization of an in vitro spinal cord slice preparation to study the opioid modulation of primary afferent dorsal horn synapses in regions of the spinal cord known to be involved in nociceptive processing. These studies stem directly from our findings in the hippocampus that LTP induction can be blocked by kappa opioids. Initial experiments using the neonatal rat transverse spinal cord slice will focus on the actions of applied mu, kappa, and delta opioids in modulating both stimulation-evoked neural excitation in lamina I of the dorsal horn and activity-dependent plastic changes in this area. These studies will use single cell extracellular recording techniques first and will benefit from the in vitro preparation in enabling application of known concentrations of agonists and antagonists to the site of action and in allowing easy visualization of the recording electrode position. Positive extracellular findings will be further evaluated using whole cell voltage clamp techniques to study post-synaptic mechanisms of action. Further, retrogradely transported fluorescent markers from rostral spinothalamic tract lesions will be used to target specific presumably nociceptive spinothalamic cell responses. The effects of endogenous mu, delta and kappa opioids on spinal neurotransmission and synaptic plasticity will then also be evaluated. Finally, these results in neonatal spinal cord will be compared and contrasted to studies using an adult spinal cord slice preparation. Thus, using an in vitro model and a variety of electrophysiological techniques, we hope to provide insight into the neurochemical mechanisms of primary afferent neurotransmission and neuroplasticity and how mu, kappa, and delta opiates differentially act to modulate these mechanisms in the adult and neonate. Such information may ultimately lead to better pharmacological means of managing and/or preventing certain acute and chronic pain states.

申请人的摘要：此申请是科学家的请求 发展奖。该奖项是为了使我的全职研究能够 关于阿片类药物对脊髓神经传递的调节作用 和突触可塑性。 这些新的研究经验 我的主持人和其他顾问的指导会为我装备 从技术和实际上讲，迅速前进，成为一个 独立研究员。 长期增强（LTP），迄今为止研究的最佳模型 中枢神经系统内的突触可塑性涉及一个看似永久的 重复激活后，神经元激发的增加 该神经元的传入输入，被认为是细胞 学习的基础。 最近的临床和行为证据 累积表明，相同的活动依赖性突触 在参与疼痛感知的神经系统中可能发生变化。 强烈的疼痛刺激会产生中央敏感性 实验动物和人类的进一步有害刺激。 这种敏化的行为药理研究表明 与LTP的神经化学相似，包括 依赖NMDA类谷氨酸受体的激活和 它的某些鸦片调节。 这里提出的研究涉及 利用体外脊髓切片准备研究 主要传入背角突触的阿片类药物调节 已知与伤害感受的脊髓区域 加工。这些研究直接源于我们在 LTP诱导的海马可以被Kappa阿片类药物阻止。 最初的 使用新生大鼠横向脊髓切片的实验将 专注于应用MU，Kappa和Delta阿片类药物的行动 调节两个刺激诱发的神经激发 背角和活动依赖性塑料在该区域变化。这些 研究将首先使用单细胞外记录技术 将从体外准备中受益，以实现 激动剂和拮抗剂的已知浓度到作用部位 并可以轻松地可视化记录电极位置。 利用整体将进一步评估阳性细胞外发现 细胞电压夹具技术研究后突触后机制 行动。此外，从 脊柱尖丘脑病变将用于靶向特定 大概是伤害性脊柱丘脑细胞反应。效果 内源性MU，三角洲和卡帕阿片类药物在脊柱神经传递和 然后，还将评估突触可塑性。最后，这些结果 在新生儿中，脊髓将被比较并与使用的研究形成对比 成人脊髓切片制剂。因此，使用体外模型和 多种电生理技术，我们希望提供洞察力 进入主要传入神经传递的神经化学机制 和神经塑性以及MU，Kappa和Delta如何差异化 采取行动以调节成人和新生儿中的这些机制。这样的 信息最终可能会导致更好的药理学手段 管理和/或防止某些急性和慢性疼痛状态。