Signaling Mechanisms of Opioid-Induced Hyperalgesia and Tolerance

阿片类药物引起的痛觉过敏和耐受性的信号机制

• 批准号: 9251088
• 负责人: Hui-Lin Pan
• 金额: $ 40.23万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251088
• 关键词: Acute; Afferent Neurons; Agonist; Analgesics; Animal Model; Attenuated; Behavioral; Cancer Etiology; Chronic; Clinical; Consumption; Data; Dependence; Development; Dose; Electrophysiology (science); Fentanyl; Genetic; Glutamates; Gold; Hyperalgesia; Hypersensitivity; Interruption; Isoenzymes; Knockout Mice; Lead; Link; Mediating; Minor; Molecular; Molecular Target; Morphine; N-Methyl-D-Aspartate Receptors; Nociception; Opioid; Opioid Analgesics; Pain; Pain management; Patients; Pharmaceutical Preparations; Phospholipase C; Play; Posterior Horn Cells; Protein Biochemistry; Protein Isoforms; Regulation; Role; Sensory; Signal Transduction; Site; Slice; Small Interfering RNA; Spinal; Spinal Cord; Spinal Ganglia; Surface; Synapses; TRPV1 gene; Testing; Therapeutic Effect; Time; Tissues; Work; cancer pain; defined contribution; design; dorsal horn; gabapentin; improved; interdisciplinary approach; knock-down; mu opioid receptors; nerve injury; novel; novel therapeutics; opioid use; painful neuropathy; phospholipase C beta; pregabalin; presynaptic; standard care; targeted treatment; trafficking; transmission process; voltage

Project Summary Opioid analgesics are the mainstay of treatment for severe pain caused by cancer and by tissue and nerve injury. However, clinical use of μ-opioid receptor agonists can cause hyperalgesia and the loss of analgesic efficacy, which lead to opioid dose escalation and remain the major obstacles to adequate pain relief with opioids. Although some evidence suggests a strong link between hyperalgesia and analgesic tolerance induced by opioids, the unifying cellular and molecular mechanisms for these two important phenomena are poorly understood. The major objective in this proposal is to identify the essential signaling mechanisms responsible for opioid-induced hyperalgesia and tolerance (OHT). Opioid administration can cause a persistent increase in glutamate release from TRPV1-expressing primary afferents through stimulation of presynaptic N-methyl-D-aspartate receptors (NMDARs), which represents a key mechanism for OHT. NMDARs are a clinically validated target for treating OHT, but little is known about how opioids lead to increased presynaptic NMDAR activity at the spinal cord level. Also, gabapentinoids can reduce OHT in animal models and in patients through a largely unknown mechanism. Our preliminary data showed that phospholipase C was critically involved in increased spinal NMDAR activity and in OHT. Furthermore, opioid-induced phospholipase C stimulation promoted the interaction between α2δ-1 and NMDARs, and such an interaction was diminished by gabapentin. In this project, we will test our central hypothesis that phospholipase C-β–dependent signaling contributes to the development of OHT predominantly by promoting α2δ-1–NMDAR interaction to increase presynaptic NMDAR activity at the spinal cord level and that gabapentin reduces OHT and spinal presynaptic NMDAR activity by interrupting α2δ-1–NMDAR interaction. We will use a multidisciplinary approach, including protein biochemistry, electrophysiological recordings in spinal cord slices, siRNA knockdown, and genetic α2δ-1 and phospholipase C-β isoform knockout mice. The proposed studies are highly significant because it will greatly advance our understanding of the fundamental signaling mechanism involved in OHT. Our findings could also help developing new therapeutic agents targeting PLC-β isozymes and α2δ-1–NMDAR interaction sites for treating OHT and reducing opioid consumption and dependence in patients.

项目摘要 阿片类镇痛药是由癌症以及组织和神经损伤引起的严重疼痛治疗的主要治疗方法。 但是，μ阿片受体激动剂的临床使用会导致痛苦和镇痛效率的丧失， 尽管这会导致卵巢剂量的升级，并且仍然是卵巢剂量充分缓解疼痛的主要障碍。 一些证据表明，阿片类药物诱导的痛性和镇痛耐受性之间有很强的联系， 对这两种重要现象的统一细胞和分子机制的理解很少。专业 该提案的目的是确定负责阿片类药物诱导的基本信号传导机制 痛苦和耐受性（OHT）。阿片类药物给药会导致谷氨酸释放的持续增加 通过刺激突触前N-甲基-D-天冬氨酸接收器来表达TRPV1的主要传入 （NMDARS），它代表了OHT的关键机制。 NMDAR是治疗OHT的临床验证目标， 但是，关于阿片类药物在脊髓水平上如何导致突触前NMDAR活性增加的知之甚少。还， gabapentinoids可以通过在很大程度上未知的机制中降低动物模型和患者的OHT。我们的 初步数据表明，磷脂酶C与脊柱NMDAR活性增加和在 OHT。此外，OIOID诱导的磷脂酶C刺激促进了α2δ-1与 NMDARS和这种相互作用被Gabapentin减少。在这个项目中，我们将检验我们的中心假设 磷脂酶C-β依赖性信号传导主要通过促进而有助于OHT的发展 α2δ-1 – NMDAR相互作用以增加突触前NMDAR在脊髓水平上的活性和Gabapentin 通过中断α2δ-1 – NMDAR相互作用来减少OHT和脊柱前NMDAR活性。我们将使用一个 多学科方法，包括蛋白质生物化学，脊髓切片中的电生理记录， siRNA敲低，遗传α2δ-1和磷脂酶C-β同工型敲除小鼠。拟议的研究是 高度重要 参与OHT。我们的发现还可以帮助开发针对PLC-β同工酶和 α2δ-1 – NMDAR相互作用位点用于治疗OHT和减少患者的阿片类药物消耗和依赖性。