Prolonged activation of endogenous opioid analgesia after inflammation

描述（由申请人提供）：外周组织炎症可导致脊髓和大脑的可塑性不良，从而导致持续疼痛。疼痛的强度和质量取决于前感觉系统与代偿性内源性抑制系统（即脊髓阿片信号）活动之间的净平衡。有趣的是，一小部分研究表明，即使在痛觉过敏的初始症状消退后，内源性阿片类药物对急性伤害感觉的抑制仍然存在。例如，阿片受体拮抗剂可以恢复异常性疼痛。这就提出了两个有趣的问题。首先，阿片受体亚型和神经回路尚不清楚。第二，在没有明显的过敏行为迹象的情况下，潜在的伤害性敏化是否会持续存在？我的初步数据显示，当足底CFA术后几周到几个月鞘内给予纳曲酮，恢复了过敏的行为迹象，并诱导背角ERK磷酸化。两者均被脊髓NMDA受体拮抗剂阻断。我的主要假设是外周炎症诱导CNS阿片能回路（Aim 1）的信号传导延长，从而掩盖了前感觉性NMDA和AMPA信号传导（Aim 2）。本F31提案试图更好地描述被内源性阿片活性掩盖的潜在致敏作用的机制。目的1验证了脊髓阿片能信号tonically掩盖伤害性致敏的假设。目标1A调查“-”、“-”和“？”-阿片受体亚型与选择性拮抗剂的使用。Aim 1B和1C在离体脊髓切片GTP的作用下检测构成受体信号传导和强直性阿片释放的机制。S35结合试验和鞘内隔离阿片肽抗血清。目的验证阿片受体阻断解除强直性传入伤害感觉假说。在目标2中，我将测试谷氨酸能信号驱动随后的超敏反应的想法

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: