Mechanisms of Spontaneous Neuropathic Pain

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理解不足。实验性神经性疼痛的特征是对有害或通常无害的感觉刺激（即异常性疼痛）的行为反应增强。这种增强反应的存在通常被认为是实验性疼痛条件的翻译和验证特征，而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，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，关于神经性疼痛的实验评估的一个关键缺陷是涉及对感觉刺激的诱发反射反应的调节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是困难的。是否介导自发性神经性疼痛的机制可能不同于那些介导损伤后增强诱发反应的机制尚不清楚。我们最近证明，将利多卡因显微注射到大脑中介导疼痛下行调节的区域（即，吻侧腹内侧髓质或RVM），在神经损伤的大鼠中产生条件位置配对（CPP）范式的偏好，但在假手术大鼠中没有。此外，我们已经表明，脊髓给药，已知产生缓解神经性疼痛的临床（即，可乐定，- concontoxin），将产生位置偏好，只在神经损伤的大鼠。在神经损伤（而非假手术）的大鼠中，在给药后表现出位置偏好，这些药物已知会激活奖赏通路和不属于奖赏通路的神经系统区域（即脑干和脊髓），这表明自发性神经性疼痛的存在和调节。虽然神经损伤引起的诱发性超敏反应（即异常性痛觉/痛觉过敏）和自发性神经性疼痛可能涉及一些共同的机制，但我们假设诱发性和自发性神经性疼痛也可以从机制上区分（如我们的初步数据所示）。本应用程序中提出的实验将通过确定以下因素的作用来探索介导自发性神经性疼痛的机制：(a)来自支配脊髓或脑干核的初级传入纤维的特异性前感觉递质（Aim 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动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。这一建议寻求新的见解，以潜在的机制之一的最重要的人类神经病变状态的症状。有关自发性疼痛的具体机制的发现将增加临床转化的机会。

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.