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的机制了解不足。实验性神经病理性疼痛的特征是对伤害性或正常非伤害性感觉刺激(即异位痛觉)的行为反应增强。这种增强反应的存在被普遍认为是实验性疼痛状况的一种翻译和验证特征，而增强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(即痛觉异常)经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为他们的神经性疼痛寻求治疗。因此，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。目前尚不清楚介导自发神经病理性疼痛的机制是否与介导损伤后增强的诱发反应的机制不同。我们最近证明，将利多卡因微量注射到大脑中介导疼痛下行调制的区域(即延髓嘴腹内侧区或RVM)，在神经损伤的大鼠中产生条件位置配对(CPP)范式的偏爱，但在假手术的大鼠中不产生偏爱。此外，我们已经证明，临床上已知能缓解神经病理性疼痛的药物(即可乐定、刀芋螺毒素)的脊髓给药只会在神经损伤的大鼠中产生位置偏爱。在神经损伤但不是假手术的大鼠中，在给予已知激活奖赏通路的药物以及神经系统(即脑干和脊髓)中不属于奖赏通路一部分的区域后，位置偏好的表现表明自发神经病理性疼痛的存在和调节。虽然神经损伤诱导的诱发超敏反应(即痛觉过敏)和自发性神经病理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病理性疼痛也可以从机械上区分(如我们的初步数据所示)。本应用中提出的实验将通过确定(A)支配脊髓或脑干核团的初级传入纤维的特异性伤害性递质(目标1)、(B)在异位放电中起重要作用的钠通道亚型(目标2)以及(C)来自RVM和脊髓水平的下行疼痛调制通路的介体来探讨自发性神经病理性疼痛的机制。目前，除了从目前使用的具有复杂药理的药物的活性中获得的有限信息外，几乎没有关于人类自发疼痛机制的信息。这项提议寻求对人类神经病状态最重要症状之一的潜在机制的新见解。与自发性疼痛的特定机制相关的发现将增加临床翻译的机会。 与公共卫生相关：神经损伤会导致一种慢性衰弱的疼痛状况，称为神经病理性疼痛，影响着数百万美国人。对这种疼痛状况的医疗是不够的，对社会的影响是巨大的，无论是从人的痛苦来衡量，还是从涉及丧失生产力和治疗的经济角度来衡量。增加对这种疼痛的机制的了解可以导致新的有效的治疗方法。

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. PUBLIC HEALTH RELEVANCE: Injuries to nerves can result in a chronic debilitating pain condition termed neuropathic pain that affects many millions of Americans. Medical treatment for this pain condition is inadequate and the impact on society is enormous whether measured in terms of human suffering or from an economic perspective involving lost productivity and treatment. Increased understanding of mechanisms of this pain condition can lead to new and effective therapy.