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: 2429988
• 负责人: GREGORY W TERMAN
• 金额: $ 14.26万
• 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/2429988
• 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.

申请人摘要：本申请是对科学家的请求 发展奖。该奖项旨在使我能够进行全职研究 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 我的导师和其他顾问的指导将装备我 在技​​术和实践上快速前进，成为 独立研究员。 长时程增强 (LTP) 是迄今为止研究最好的模型 中枢神经系统内的突触可塑性涉及看似永久性的 重复激活后神经元兴奋增加 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表明 累积表明，同样的活动依赖性突触 与疼痛感知有关的神经系统可能会发生变化。 强烈的疼痛刺激可以产生中枢敏化 对实验动物和人类的进一步有害刺激。 这种致敏作用的行为药理学研究表明 与 LTP 的神经化学有许多相似之处，包括 依赖于 NMDA 类谷氨酸受体的激活 它通过某些阿片类药物进行调节。 这里提出的研究涉及 利用体外脊髓切片制剂进行研究 阿片类药物对初级传入背角突触的调节 已知参与伤害感受的脊髓区域 加工。这些研究直接源于我们的研究结果 海马中的 LTP 诱导可以被 kappa 阿片类药物阻断。 最初的 使用新生大鼠横向脊髓切片的实验将 重点关注所应用的 mu、kappa 和 delta 阿片类药物的作用 调节刺激引起的第一层神经兴奋 背角和该区域活动依赖性的塑性变化。这些 研究将首先使用单细胞细胞外记录技术 将受益于体外制剂的应用 作用位点的已知浓度的激动剂和拮抗剂 并允许轻松可视化记录电极位置。 阳性细胞外发现将使用整体进一步评估 细胞电压钳技术研究突触后机制 行动。此外，逆行转运荧光标记 脊髓丘脑头端束病变将用于针对特定的目标 推测是伤害性脊髓丘脑细胞反应。的影响 内源性 mu、delta 和 kappa 阿片类药物对脊髓神经传递的影响 然后还将评估突触可塑性。最后，这些结果 将与使用新生儿脊髓的研究进行比较和对比 成人脊髓切片的制备。因此，使用体外模型和 各种电生理技术，希望提供见解 初级传入神经传递的神经化学机制 和神经可塑性以及 mu、kappa 和 delta 阿片类药物有何不同 调节成人和新生儿的这些机制。这样的 信息可能最终导致更好的药理学手段 管理和/或预防某些急性和慢性疼痛状态。