Endovanilloid-Mediated Modulation and its Role in Habituation and Sensitization

慢性疼痛是美国医疗保健的主要负担，每年影响约1亿人 耗资6350亿美元。该提案将研究痛觉信号(伤害感)的调制作为学习的一种形式。 和记忆。伤害性记忆的获得代表了敏感型学习的一种形式 无论是对伤害性刺激(痛觉过敏)的反应增加，还是有非伤害性刺激引起 疼痛反应(超常疼痛)。另一方面，习惯化是一种潜在的消除伤害感受器的机制。 并且可能代表一种未被识别的过程，该过程有助于止痛调制的形式，例如 门控制疼痛或应激诱导的止痛。这种方法的好处不仅在于理解疼痛-- 诱导敏感化发展，但也在潜在地使用基于学习的方法来减少疼痛，例如 使用习惯化来减少伤害性环路的活动。 我们已经确定了一个调节过程，特别是通过瞬时受体作用的内源性大麻素。 潜在的香草酸(TRPV)通道，有助于疼痛相关的敏感化和疼痛的习惯化- 唤起的行为。内源性大麻素是一种脂类神经递质，可以激活任何一种代谢性大麻素 受体(CB1和CB2)或TRPV通道(在这种情况下，内源性大麻素有时被称为 香草素)。虽然人们对基于大麻素的疗法很感兴趣，但它们在 治疗慢性疼痛是值得怀疑的。这在一定程度上是因为内源性大麻素既能起到抗伤害作用，又能起到抗伤害作用。 以及促进伤害的作用。内源性大麻素可以抑制伤害性突触(一种抗伤害性作用) 我们有证据表明，这种调节过程有助于重复的非痛苦刺激的能力 减少对疼痛刺激的反应，这是习惯化的一种形式。内源性大麻素也介导突触 去抑制/增强非伤害性突触，这是一种可能导致疼痛的前伤害性效应- 诱导敏化。在这项研究中，我们将研究内源性大麻素和TRPV信号在 与伤害性有关的敏化和习惯化使用水牛(药用水蛭)。这种方法 充分利用了我们已经识别出的独特的水貂神经系统 突触经历内源性大麻素/TRPV介导的抑制或去抑制/增强。一个 另一个优点是水貂缺乏CB1和CB2受体，因此有可能分离出CB1和CB2的作用 内源性大麻素通过TRPV起作用。在目标1中，介导内源性大麻素/TRPV的细胞机制- 我们将研究非伤害性突触的诱导增强，以及这种可塑性如何对 对非痛性刺激(痛觉异常)敏感。在目标2中，内源性大麻素/TRPV介导的抑郁的作用 将研究习惯化过程中伤害性突触的变化，以及这种习惯化是否可以逆转损伤- 诱导敏化。目标3将解决是什么控制抗伤害性或亲伤害性的问题。 伤害性形式的内源性大麻素/TRPV调制被启动。这将集中于以下潜在角色： 内源性大麻素递质的不同来源以及不同的传入活动模式如何触发 负责内源性大麻素合成或翻译后修饰的蛋白质的基因表达 这些相同的蛋白质。 这些研究将产生以下影响。首先，用习惯化的方法“抹去”伤害感受器 记忆是一种新的方法，可以通过修改现有的医学方法立即用于人类 设备疗法，例如经皮电神经刺激(TENS)疗法，使其更有效。 第二，内源性大麻素有助于TENS启动的神经调节过程 疗法可能会提供一种途径，将基于内源性大麻素的药物(迄今未能成功)与 这种基于医疗器械的疗法，产生了任何一种方法都不能单独产生的止痛效果。 最后，关于基于大麻素的疗法的有效性的问题无疑是基于它们的能力。 通过伤害性回路增加和减少活动。解决细胞机制的中介作用 如果基于大麻素的疗法要有效地治疗疼痛，这些相反的影响是至关重要的。

Chronic pain is a major health care burden in the US, affecting approximately 100 million people at an annual cost of $635 billion. This proposal will examine modulation in pain signaling (nociception) as a form of learning and memory. Acquisition of a nociceptive memory represents a form of sensitization-type learning involving either an increased response to nociceptive stimuli (hyperalgesia) or having non-nociceptive stimuli elicit a painful response (allodynia). Habituation, on the other hand, is a potential mechanism to erase a nociceptive memory and may represent an unrecognized process contributing to forms of analgesic modulation such as gate-control of pain or stress-induced analgesia. This approach has benefits not only in understanding how pain- induced sensitization develops, but also in potentially using learning-based approaches to reduce pain, such as using habituation to reduce activity in nociceptive circuits. We have identified a modulatory process, specifically endocannabinoids acting through Transient Receptor Potential Vanilloid (TRPV) channels, that contributes to both pain-related sensitization and habituation of pain- evoked behaviors. Endocannabinoids are lipid neurotransmitters that activate either metabotropic cannabinoid receptors (CB1 and CB2) or TRPV channels (in which case endocannabinoids are sometimes referred to as endovanilloids). While there is considerable interest in cannabinoid-based therapies, their effectiveness in treating chronic pain is questionable. This is, in part, because endocannabinoids can exert both anti-nociceptive and pro-nociceptive effects. Endocannabinoids can depress nociceptive synapses (an anti-nociceptive effect) and we have evidence that this modulatory process contributes the ability of repetitive non-painful stimuli to reduce responses to painful stimuli, a form of transfer of habituation. Endocannabinoids also mediate synaptic disinhibition/potentiation of non-nociceptive synapses, a pro-nociceptive effect that may contribute to pain- induced sensitization. In this study, we will examine the role of endocannabinoids and TRPV signaling during nociception-related sensitization and habituation using Hirudo verbana (the medicinal leech). This approach takes advantage of the well-characterized nervous system of Hirudo in which we have already identified distinct synapses that undergo either endocannabinoid/TRPV-mediated depression or disinhibition/potentiation. An additional advantage is that Hirudo lacks CB1 and CB2 receptors, so it is possible to isolate the role of endocannabinoids acting via TRPV. In Aim 1, the cellular mechanisms mediating endocannabinoid/TRPV- induced potentiation of non-nociceptive synapses will be examined as well as how this plasticity contributes to sensitization to non-painful stimuli (allodynia). In Aim 2, the role of endocannabinoid/TRPV-mediated depression of nociceptive synapses during habituation will be studied as well as whether this habituation can reverse injury- induced sensitization. Aim 3 will address the question of what controls whether the anti-nociceptive or pro- nociceptive forms of endocannabinoid/TRPV modulation are initiated. This will focus on the potential roles of distinct sources of endocannabinoid transmitters and how different patterns of afferent activity can trigger either gene expression of proteins responsible for endocannabinoid synthesis or post-translational modification of these same proteins. These studies will have the following impact. First, using habituation approaches to “erase” a nociceptive memory is a novel approach and one that could be used immediately in humans by modifying existing medical device therapies, e.g., transcutaneous electrical nerve stimulation (TENS) therapy, making them more effective. Second, the idea that endocannabinoids contribute to the neuromodulatory processes initiated by TENS therapies may provide an avenue for combining endocannabinoid-based drugs (which have failed to date) with this medical device-based therapy, producing an analgesic effect that neither approach can produce on its own. Finally, questions about the effectiveness of cannabinoid-based therapies is undoubtedly based on their ability to both increase and decrease activity by nociceptive circuits. Resolving the cellular mechanisms that mediate these opposing effects is critical if cannabinoid-based therapies are to be effective for treating pain.