Mechanisms of Spontaneous Neuropathic Pain

自发性神经病理性疼痛的机制

• 批准号: 8470257
• 负责人: Frank Porreca
• 金额: $ 31.19万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8470257
• 关键词: 6-Cyano-7-nitroquinoxaline-2,3-dione; Address; Adenosine; Affect; Afferent Pathways; American; Animal Model; Animals; Area; Axotomy; Behavior; Behavioral; Bradykinin B2 Receptor; Bradykinin Receptor; Brain; Brain Stem; Calcium Channel Blockers; Caliber; Cell Nucleus; Cholecystokinin; Cholecystokinin B Receptor; Chronic; Clinical; Clonidine; Communities; Complex; Conotoxin; Cues; Data; Drug Delivery Systems; Drug Industry; Dynorphins; Economics; Elan brand of omega-conopeptide MVIIA; Erythromelalgia; Evaluation; Fiber; Filament; Gene Targeting; Glutamates; Heating; Human; Human Genetics; Hyperalgesia; Hypersensitivity; Immune Sera; Inherited; Injury; Intervention; Ketamine; Lead; Lesion; Lidocaine; Ligation; Link; Literature; Measurement; Measures; Mediating; Mediator of activation protein; Medical; Microinjections; Modeling; Molecular Target; Mutation; N-Methylaspartate; N-Type Calcium Channels; Nerve; Nervous system structure; Neuropathy; Nociception; Ondansetron; Pain; Pain management; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Peripheral nerve injury; Pharmaceutical Preparations; Pharmacology; Predictive Value; Procedures; Productivity; Rattus; Reporting; Rewards; Role; Self Administration; Self-Administered; Sensory Thresholds; Site; Societies; Sodium Channel; Spinal; Spinal Cord; Spinal nerve structure; Stimulus; Symptoms; Tactile; Testing; Thermal Hyperalgesias; Touch sensation; Translations; Up-Regulation; Withdrawal; Work; allodynia; base; chronic neuropathic pain; chronic pain; clinically relevant; dorsal horn; drug discovery; effective therapy; experience; human data; in vivo; injured; insight; kainate; knock-down; nerve injury; pain behavior; painful neuropathy; preclinical study; preference; public health relevance; receptor; research study; response; sensory stimulus; spontaneous pain; transmission process; ziconotide

DESCRIPTION (provided by applicant): Current options for treatment of neuropathic pain remain unsatisfactory in part because of an inadequate understanding of mechanisms of this abnormal pain condition. Experimental neuropathic pain is characterized by the presence of enhanced behavioral responses to noxious or normally non-noxious sensory stimuli (i.e., allodynia). The presence of such enhanced responses is generally accepted as a translational and validating feature of the experimental pain condition and modulation of enhanced sensory thresholds is commonly used to explore mechanisms relevant to potential therapy. Studies in humans, however, have shown that changes in evoked thresholds (i.e., allodynia) frequently do not correlate with reductions in pain scores. Rather, it is the spontaneous aspects of the human pain experience that lead patients to seek treatment for their neuropathic pain. Thus, a critical shortcoming with regard to experimental evaluation of neuropathic pain is the reliability and predictive value of studies involving modulation of evoked reflexive responses to sensory stimuli and subsequent interpretation of mechanism. Experimental measurement of spontaneous pain following peripheral nerve injury has been difficult. Whether mechanisms which mediate spontaneous neuropathic pain may be distinct from those mediating enhanced evoked responses following injury is not known. We have recently demonstrated that microinjection of lidocaine into an area of the brain that mediates descending modulation of pain (i.e., the rostral ventromedial medulla or RVM) produces preference in a conditioned place pairing (CPP) paradigm in nerve injured, but not in sham-operated, rats. Additionally, we have shown that spinal administration of drugs that are known to produce relief of neuropathic pain clinically (i.e., clonidine, -conotoxin), will produce place preference only in nerve injured rats. The demonstration of place preference in nerve-injured, but not sham-operated, rats following administration of drugs which are known to activate reward pathways and in areas of the nervous system (i.e., brainstem and spinal cord) which are not a part of the reward pathway suggests the presence and modulation of spontaneous neuropathic pain. While nerve injury-induced evoked hypersensitivity (i.e., allodynia/hyperalgesia) and spontaneous neuropathic pain are likely to involve some common mechanisms, we hypothesize that evoked and spontaneous neuropathic pain can also be distinguished mechanistically (as shown by our preliminary data). The experiments proposed in this application will explore the mechanisms mediating spontaneous neuropathic pain by determining the role of (a) specific pronociceptive transmitters from primary afferent fibers innervating the spinal cord or brainstem nuclei (Aim 1), (b) subtypes of sodium channels which important in ectopic discharge (Aim 2) and (c) mediators of the descending pain modulatory pathway from the RVM and at the level of the spinal cord. At present, almost no information is known about mechanisms of human spontaneous pain beyond the limited information gained from the activity of currently employed medications that have complex pharmacology. This proposal seeks new insights into potential mechanisms of one of the most important symptoms of the human neuropathic state. Discoveries related to specific mechanisms of spontaneous pain will increase opportunities for clinical translation.

描述（由申请人提供）：目前治疗神经性疼痛的选择仍然不令人满意，部分原因是对这种异常疼痛状况的机制了解不足。实验性神经性疼痛的特征在于存在对有害或通常无害的感觉刺激的增强的行为反应（即，异常性疼痛）。这种增强的反应的存在通常被接受为实验性疼痛状况的转化和验证特征，并且增强的感觉阈值的调节通常用于探索与潜在治疗相关的机制。然而，对人类的研究表明，诱发阈值的变化（即，异常性疼痛）通常与疼痛评分的降低无关。相反，正是人类疼痛体验的自发方面导致患者寻求治疗他们的神经性疼痛。因此，神经性疼痛的实验评价的一个关键缺点是涉及对感觉刺激的诱发反射反应的调制和随后的机制解释的研究的可靠性和预测价值。周围神经损伤后自发性疼痛的实验测量一直很困难。介导自发性神经性疼痛的机制是否与介导损伤后诱发反应增强的机制不同尚不清楚。我们最近已经证明，将利多卡因微量注射到介导疼痛下行调制的大脑区域（即，延髓头端腹内侧区（RVM）在神经损伤的条件位置配对（CPP）模式中产生偏好，但在假手术大鼠中不产生。此外，我们已经表明，已知在临床上产生神经性疼痛缓解的药物的脊柱给药（即，可乐定、-芋螺毒素）仅在神经损伤的大鼠中产生位置偏爱。在给予已知激活奖赏途径的药物后，在神经损伤但非假手术的大鼠中以及在神经系统的区域（即，脑干和脊髓），其不是奖赏途径的一部分，提示自发性神经性疼痛的存在和调节。而神经损伤诱导的诱发超敏反应（即，异常性疼痛/痛觉过敏）和自发性神经性疼痛可能涉及一些共同的机制，我们假设诱发性和自发性神经性疼痛也可以在机制上区分（如我们的初步数据所示）。本申请中提出的实验将通过确定（a）来自支配脊髓或脑干核的初级传入纤维的特异性原伤害感受递质的作用来探索介导自发性神经性疼痛的机制（目的1），（B）在异位放电中重要的钠通道亚型（Aim 2）和（c）RVM和脊髓水平的下行疼痛调节通路的介质。目前，除了从目前使用的具有复杂药理学的药物活性中获得的有限信息外，几乎没有关于人类自发性疼痛机制的信息。该提案旨在对人类神经病状态最重要症状之一的潜在机制进行新的见解。与自发性疼痛的特定机制相关的发现将增加临床转化的机会。