Calcineurin and Neuropathic Pain

钙调神经磷酸酶和神经性疼痛

• 批准号: 8278222
• 负责人: VJEKOSLAV MILETIC
• 金额: $ 32.92万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278222
• 关键词: A kinase anchoring protein; AMPA Receptors; Acute; Analgesics; Animals; Attenuated; Biological; Brain; Calcineurin; Calcineurin inhibitor; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Development; Exhibits; Family; Frequencies; Goals; Hippocampus (Brain); Inflammation; Injury; Intrathecal Injections; Ipsilateral; Knowledge; Lead; Ligation; Link; Mediating; Membrane; Metabotropic Glutamate Receptors; N-Methylaspartate; Peripheral nerve injury; Persistent pain; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Posterior Horn Cells; Protein Dephosphorylation; Protein phosphatase; Proteins; Role; Scaffolding Protein; Sensory; Sensory Process; Specificity; Spinal; Spinal nerve structure; Synapses; Synaptic plasticity; Therapeutic; chronic constriction injury; density; dorsal horn; long term memory; nerve injury; novel; pain behavior; painful neuropathy; prevent; response; sciatic nerve

DESCRIPTION (provided by applicant): Calcineurin (protein phosphatase 3, previously protein phosphatase 2B) plays a pivotal role in regulating activity-dependent synaptic plasticity in the brain. The development of neuropathic pain appears dependent upon some of the same mechanisms that underlie brain synaptic plasticity. Much progress has been made in elucidating some of these mechanisms but many gaps in our knowledge remain. As a result neuropathic pain continues to be inadequately treated. In this application we wish to fill in some of these gaps as we seek to elucidate whether calcineurin plays a role in regulating injury-elicited plasticity in the spinal dorsal horn. Our preliminary data revealed significantly lower calcineurin activity and content in the ipsilateral post-synaptic density (PSD) of spinal dorsal horn neurons in animals exhibiting neuropathic pain behavior following chronic constriction injury (CCI) of the sciatic nerve or spinal nerve ligation (SNL). The pain behavior after CCI was attenuated by an intrathecal injection of exogenous calcineurin. An intrathecal application of the calcineurin inhibitor FK-506 elicited pain behavior in control, uninjured animals. These data suggested a connection between calcineurin and neuropathic pain but it remains unclear how the loss of the phosphatase in the PSD may influence the development of neuropathic pain. In this application we postulate at least three negative consequences of calcineurin's loss. Disruption of a complex formed by the A kinase anchoring protein (AKAP), protein kinase A (PKA) and calcineurin (Aim 1). Persistent phosphorylation and insertion of AMPA receptors in the PSD membrane (Aim 2). Phosphorylation-dependent physical linking of AMPA, NMDA and metabotropic glutamate receptor (mGluR) families through the establishment or enhancement of links between the scaffolding proteins PSD-95, Shank and Homer (Aim 3). In addition, in the brain a loss of calcineurin activity at hippocampal synapses permits the transition from short to long-term memory. It is tempting to hypothesize that the transition to neuropathic pain is a consequence of the loss of calcineurin from the PSD of spinal dorsal horn neurons (Aim 4). Calcineurin activity in the PSD may critically constrain high-frequency afferent activity from eliciting long-lasting plasticity because the latter may signify the development of neuropathic pain. In other words, nerve injury may give rise to neuropathic pain at least in part as a result of the loss of calcineurin-mediated dephosphorylation in the spinal dorsal horn. With no dephosphorylation to prevent a remodeling of the PSD which favors synaptic enhancement only exaggerated evoked responses would be elicited by primary afferent activity. This enhanced sensory input manifests then as neuropathic pain. Overall we strive to achieve two goals. From a cellular perspective we wish to delineate the consequences of nerve injury on the protein matrix of the PSD in spinal dorsal horn neurons. From a therapeutic perspective we seek better target specificity for more effective analgesic treatments. PUBLIC HEALTH RELEVANCE: The processing of sensory information in the spinal dorsal horn may change significantly following peripheral nerve injury or inflammation to ultimately lead to the development of neuropathic pain. For example, a short but intense period of acute injury to the sciatic nerve may lead to persistent pain that far outlasts the initial insult. Much progres has been made in elucidating some of the mechanisms underlying the development of neuropathic pain. Yet, many gaps in our knowledge remain and as a result neuropathic pain continues to be inadequately treated. In this application we strive to achieve two goals. From a biological perspective we wish to fill in some of the gaps in our understanding of the mechanisms of neuropathic pain. From a therapeutic perspective we seek novel targets for more effective analgesic treatments.

描述（由申请人提供）：钙调神经酶（蛋白质磷酸酶3，先前蛋白质磷酸酶2B）在调节大脑中活性依赖性突触可塑性方面起关键作用。神经性疼痛的发育似乎取决于脑突触可塑性构成的一些相同机制。在阐明其中一些机制方面取得了很多进展，但我们的知识中仍然存在许多差距。结果，神经性疼痛继续治疗不足。在此应用中，我们希望填补其中的一些空白，因为我们试图阐明钙调神经酶是否在调节脊柱背角中的损伤引诱的可塑性中起作用。我们的初步数据显示钙调神经素明显降低 在肌肉神经或脊柱神经结扎术（SNL）的慢性狭窄损伤（CCI）后，脊柱背角神经元的同侧后突触后密度（PSD）中的活性和含量表现出神经性疼痛行为。 CCI后的疼痛行为通过鞘内注射外源性钙调蛋白的抑制作用。钙调神经蛋白抑制剂FK-506的鞘内应用引起对照，无受伤的动物的疼痛行为。这些数据表明钙调神经酶与神经性疼痛之间存在联系，但尚不清楚PSD中磷酸酶的丧失如何影响神经性疼痛的发展。在此应用中，我们假设钙调神经素损失至少三个负面后果。由A激酶锚定蛋白（AKAP），蛋白激酶A（PKA）和钙调神经酶（AIM 1）形成的复合物的破坏。 AMPA受体在PSD膜中的持续磷酸化和插入（AIM 2）。通过建立或增强脚手架蛋白PSD-95，Shank和Homer之间联系的AMPA，NMDA和代谢型谷氨酸受体（MGLUR）家族的磷酸化依赖性物理联系（MGLUR）家族（AIM 3）。此外，在大脑中，海马突触中钙调神经素活性的丧失允许从短期到长期记忆的过渡。很容易假设向神经性疼痛的过渡是脊髓背角神经元PSD失去钙调蛋白的结果（AIM 4）。钙调神经酶活性 PSD可能会严重限制高频传入活性，从而引起长期可塑性，因为后者可能表示神经性疼痛的发展。换句话说，神经损伤可能至少部分导致神经性疼痛导致脊柱背侧角中钙调蛋白介导的去磷酸化。没有去磷酸化以防止对PSD进行重塑，而PSD只有夸张的诱发反应才能通过一级传入活性引起。然后，这种增强的感觉输入表现为神经性疼痛。总体而言，我们努力实现两个目标。从细胞的角度来看，我们希望描述脊髓背角神经元中PSD蛋白质基质的神经损伤的后果。从治疗的角度来看，我们寻求更好的目标特异性来进行更有效的镇痛治疗。 公共卫生相关性：在周围神经损伤或炎症之后，脊柱角角中感觉信息的处理可能会发生显着变化，以最终导致神经性疼痛的发展。例如，坐骨神经的短暂但严重的急性损伤可能会导致持续的疼痛，这远远超过了最初的侮辱。在阐明神经性疼痛发展的基本机制方面已经做出了许多预科。然而，我们所知的许多差距仍然存在，因此神经性疼痛继续受到不足的治疗。在此应用程序中，我们努力实现两个目标。从生物学的角度来看，我们希望填补我们对神经性疼痛机制的理解中的一些空白。从治疗的角度来看，我们寻求新的靶标的更有效的镇痛治疗。