Stress-induced descending facilitation from amygdala kappa opioid receptors in functional pain

项目摘要 许多患者在没有可识别的损伤的情况下遭受慢性疼痛。这种疼痛被称为“功能性”。 包括肠易激综合征、颞下颌关节紊乱、纤维肌痛、偏头痛等。 功能性疼痛患者经历的无痛期会被疼痛发作所打断，这种疼痛可以持续 可变的时间段。这些疼痛障碍的时序化与疼痛的数量和频率有关 表明反复的伤害性发作促进并维持中枢敏感化状态 这反映出对未来攻击的脆弱性增加。功能性疼痛患者通常认为压力是关键 疼痛发作的触发因素，但神经生物学机制仍有待确定。 在这个项目中，我们测试了一种新的假设，即在致敏状态下，应激诱导的kappa阿片受体(Kor) 杏仁核中的信号促进功能性疼痛反应。我们开发了一种无损伤的啮齿动物模型 基于阿片类药物痛觉过敏的应激相关功能性疼痛。阿片类药物已被证明可以 在人类和动物身上产生阿片诱导的痛敏(OIH)。OIH的特点是泛化 触觉和热痛觉过敏，痛觉阈值降低，时间总和增加，以及 下行有害抑制对照(DNIC)。在OIH解决后，在没有应激的情况下，动物 有正常的疼痛反应。然而，过敏性启动会产生一种潜伏的敏化状态，从而 以前接触吗啡的动物现在容易出现应激诱导的痛觉过敏和DNIC的丢失，DNIC 通过阻断杏仁中央核(CEA)内的KOR信号而被阻止。我们的 电生理数据支持KOR介导的对促进疼痛的CEA神经元的去抑制。 我们将使用先进的行为和电生理方法以及光遗传学和化学遗传学 方法证明未经免疫刺激的对照小鼠的CEA KOR神经元的激活促进了疼痛相关 答复(具体目标1)。这些研究将建立杏仁核内可能存在的神经回路。 一种新的KOR介导的前伤害性CEA输出，通过去抑制进行。特定目标2将 确定外源性激活CEA-KOR环路是否会导致预充后疼痛反应的放大- 诱导潜伏性敏化。在特定的目标3中，我们将确定应激诱导的内源性阻断 CEA-KOR信号通路可减少启动诱导的潜伏敏化后的疼痛反应。 拟议的研究将描述一种以前未知的与压力相关的KOR介导的痛觉过敏电路 并确定这一回路可能如何促进对压力的弹性降低。重要的是，这些研究 可能通过一种机制来揭示应激相关功能性疼痛障碍的治疗干预机制 可操作的分子靶标。KR拮抗剂目前正在开发中。

Project Summary Many patients suffer from chronic pain in the absence of identifiable injury. Such pains are termed “functional” and include irritable bowel syndrome, temporomandibular joint disorder, fibromyalgia, migraine and others. Functional pain patients experience pain free periods that are interrupted by attacks of pain that can persist for variable periods of time. The chronification of these pain disorders has been linked to the number and frequency of attacks suggesting that repeated nociceptive episodes promote and maintain a state of central sensitization that reflects increased vulnerability to future attacks. Functional pain patients commonly identify stress as a key trigger of pain episodes but neurobiological mechanisms remain to be determined. In this project, we test the novel hypothesis that in sensitized states, stress-induced kappa opioid receptor (KOR) signaling in the amygdala promotes functional pain responses. We have developed an injury-free rodent model of stress-related functional pain based on hyperalgesic priming with opioids. Opioids have been shown to produce opioid-induced hyperalgesia (OIH) in humans and in animals. OIH is characterized by generalized tactile and thermal hyperalgesia, decreased nociceptive thresholds, increase temporal summation, and a loss of descending noxious inhibitory controls (DNIC). Following resolution of OIH, and in the absence of stress, animals have normal pain responses. Hyperalgesic priming, however, produces a state of latent sensitization so that animals previously exposed to morphine are now prone to stress-induced hyperalgesia and a loss of DNIC that is prevented by blockade of KOR signaling within the central nucleus of the amygdala (CeA). Our electrophysiological data support a KOR-mediated disinhibition of CeA neurons that promote pain. We will use advanced behavioral and electrophysiological approaches with optogenetic and chemogenetic methods to demonstrate that activation of CeA KOR neurons in control, unprimed mice promotes pain-related responses (Specific Aim 1). These studies will establish the neural circuitry within the amygdala that may underlie a novel KOR-mediated pronociceptive CeA output that is engaged through disinhibition. Specific Aim 2 will determine if exogenous activation of the CeA KOR circuit results in amplified pain responses following priming- induced latent sensitization. In Specific Aim 3 we will determine whether blockade of stress-induced endogenous CeA KOR signaling reduces pain responses following priming-induced latent sensitization. The proposed studies will characterize a previously unknown stress-related KOR mediated hyperalgesic circuit from CeA and determine how this circuit may promote decreased resilience to stress. Importantly, these studies may unravel mechanisms for therapeutic interventions in stress-related functional pain disorders through an actionable molecular target. KOR antagonists are currently in development.