Prolonged activation of endogenous opioid analgesia after inflammation

描述(申请人提供)：外周组织炎症可导致脊髓和大脑的不适应可塑性，从而导致持续性疼痛。疼痛的强度和质量由前伤害性感觉系统和代偿性内源性抑制系统(即脊髓阿片信号)之间的净平衡决定。有趣的是，一小组研究表明，内源性阿片类药物对急性伤害性感觉的抑制即使在痛觉过敏的最初迹象消退后仍然存在。例如，阿片受体拮抗剂可以恢复痛觉异常。这引发了两个耐人寻味的问题。首先，阿片受体亚型和神经回路仍不清楚。第二，在没有明显的过敏性行为迹象的情况下，潜在的伤害性敏感化是否持续？我的初步数据显示，在足底CFA后几周到几个月的时间里，鞘内注射纳曲酮，可以恢复行为过敏的迹象，并诱导背角ERK磷酸化。两者都被NMDA受体的脊髓拮抗作用所阻断。我的中心假设是，外周炎症诱导了中枢阿片能回路(目标1)的延长信号，从而掩盖了伤害性前体NMDA和AMPA信号(目标2)。这项F31提案试图更好地描述被内源性阿片类药物活性掩盖的潜在敏化的机制。目的1验证脊髓阿片能信号调强掩饰伤害性敏感化的假说。目的研究选择性拮抗剂对阿片受体亚型的影响。目的用体外脊髓切片GTP、S35结合实验和鞘内阿片肽抗血清分别检测构成受体信号转导和紧张性阿片释放的机制。目的1D验证阿片受体阻断剂抑制紧张性传入伤害性感觉的假说。在目标2中，我将测试谷氨酸能信号驱动紧随其后的超敏反应的想法 脊髓阿片受体阻断，重点是脊髓NMDA(Aim 2A)和AMPA/海人藻酸受体(Aim 2B)。通过更好地了解长期的阿片类药物抗伤害感受，该项目可能为未来加强慢性疼痛患者内源性阿片类药物镇痛的策略铺平道路，从而具有揭示防止急性疼痛向慢性疼痛过渡的新靶点的长期潜力。这个F31奖项将帮助我实现我的目标，使我能够成功竞争强大的博士后职位，并最终在强大的医学研究型大学环境中从终身教职开始，在研究科学和教学领域取得成功的职业生涯： 与公共卫生相关：在组织炎症的背景下，疼痛通路的敏感化导致一种超敏状态，这种状态被代偿性内源性抑制系统抵消。该项目旨在了解脊髓阿片系统掩盖长期谷氨酸敏化的机制。旨在增强这种内源性阿片信号的治疗策略可能会减少持续性疼痛的发生。

DESCRIPTION (provided by applicant): Peripheral tissue inflammation can lead to maladaptive plasticity in the spinal cord and brain which contributes to persistent pain. The intensity and quality of pain is determined by the net balance between the activities of pronociceptive systems with compensatory endogenous inhibitory systems, namely spinal opioid signaling. Interestingly, a small set of studies indicate that endogenous opioid inhibition f acute nociception persists even after the initial signs of hyperalgesia have subsided. For example, opioid receptor antagonists reinstate allodynia. This raises two intriguing questions. First, opioid receptor subtypes and neural circuits remain unclear. Second, does a latent nociceptive sensitization persist in the absence of overt behavioral signs of hypersensitivity? My preliminary data show that naltrexone, when intrathecally administered weeks to months after intraplantar CFA, reinstated behavioral signs of hypersensitivity and induced dorsal horn ERK phosphorylation. Both were blocked by spinal antagonism of NMDA receptors. My central hypothesis is that peripheral inflammation induces prolonged signaling of CNS opioidergic-circuits (Aim 1) that mask pronociceptive NMDA and AMPA signaling (Aim 2). This F31 proposal attempts to better characterize the mechanisms that underlie the latent sensitization that is masked by endogenous opioid activity. Aim 1 tests the hypothesis that spinal opioidergic signaling tonically masks nociceptive sensitization. Aim 1A investigates ¿-, ¿-, and ?-opioid receptor subtypes with the use of selective antagonists. Aim 1B and 1C test mechanisms of constitutive receptor signaling and tonic opioid release with the use of ex vivo spinal cord slice GTP ?S35 binding assay and intrathecal sequestering opioid peptide antiserum, respectively. Aim 1D tests the hypothesis that opioid receptor blockade disinhibits tonic afferent nociception. In Aim 2 I will test the idea that glutamatergic signaling drives the hypersensitivity that follows spinal opioid receptor blockade, with a focus on spinal NMDA (Aim 2A) and AMPA/kainate-receptors (Aim 2B). By better understanding long-lasting opioid antinociception, this project could pave the way for future strategies to enhance endogenous opioid analgesia in humans with chronic pain, and thus has the long-term potential to reveal novel targets to prevent the transition for acute to chronic pain. This F31 award will help me achieve my goals that will enable me to successfully compete for strong post-doctoral positions and ultimately, a successful career in research science and teaching beginning with a tenure-track position in a strong medical research university environment: PUBLIC HEALTH RELEVANCE: Sensitization of pain pathways, in the setting of tissue inflammation, leads to a state of hypersensitivity that is counteracted by compensatory endogenous inhibitory systems. This project aims to understand the mechanisms by which the spinal opioid system masks long-lasting glutamatergic sensitization. Therapeutic strategies designed to enhance this endogenous opioid signaling may reduce the occurrence of persistent pain.