Alternatives to prescription opioids: a precision medicine approach to harnessing endogenous opioids for pain relief and circumvention of prescription opioid abuse

处方阿片类药物的替代品：利用内源性阿片类药物缓解疼痛和规避处方阿片类药物滥用的精准医学方法

• 批准号: 9303135
• 负责人: ALAN R GINTZLER
• 金额: $ 36.56万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303135
• 关键词: Absence of pain sensation; Acute Pain; Analgesics; Anatomy; Anus; Aromatase; Aromatase Inhibitors; Behavioral; Closure by clamp; Co-Immunoprecipitations; Coupled; Data; Diestrus; Dynorphins; Effectiveness; Electrophoresis; Epidemic; Estrogen Receptor alpha; Estrogens; Estrous Cycle; Estrus; Etiology; Failure; Female; Functional disorder; Gel; Glutamates; Image; Immunohistochemistry; Intervention; Ligands; Lysophospholipase; Mass Spectrum Analysis; Membrane; Menstrual cycle; Metabotropic Glutamate Receptors; Modeling; Molecular; Molecular Target; Names; Nature; Neurons; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Pathway interactions; Pharmacology; Pharmacotherapy; Phase; Phenotype; Phospholipase C; Phosphorylation; Physiological; Proestrus; RNA; Rattus; Recruitment Activity; Research; SRC gene; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Site; Spinal; Spinal Cord; System; Testing; Vision; Woman; base; behavior test; beta-arrestin; chronic pain; endogenous opioids; experience; gel electrophoresis; knock-down; male; men; metabotropic glutamate receptor 2; molecular drug target; mu opioid receptors; new therapeutic target; novel; precision medicine; prescription opioid; prescription opioid abuse; response; sex

Estrous (menstrual) cycle and estrogens influence pain sensitivity and analgesic effectiveness of µ-opioid re- ceptor (MOR)-selective opioids, e.g., our recent finding that the analgesia elicited in female rats by the in- trathecal (i.t.) application of the endogenous MOR ligand endomorphin 2 (EM2) is dampened during diestrus but robust and comparable to that of males during proestrus. Uncovering the molecular bases for clamped spi- nal EM2 analgesia will reveal novel molecular targets for drug interventions that disinhibit, and thus harness, endogenous EM2 analgesia, lessening the use of prescription opioids, and thereby their abuse. The organizing rubric generating Aims is that the phasic nature of spinal EM2 analgesia over the estrous cycle results from the plasticity of interactions among spinal MOR, κ-opioid receptor (KOR), aromatase (Aro), membrane estrogen receptor α (mERα), mGluRs and their associated signaling partners. The first three aims focus on the molecu- lar components (and their organization) that regulate i.t. EM2 analgesia. The fourth aim investigates transla- tional relevance of findings. Aim 1 tests the hypothesis that during diestrus, spinal mERα-mGluR1 signaling, via phospholipase C and β−arrestin, dampens spinal EM2 analgesia. Aim 2 tests the hypothesis that during proestrus, mERα and β−arrestin are no longer relevant to spinal EM2 analgesia; mGluR1 now organizes with mGluR2/3 to signal via c-Src, facilitating spinal dynorphin release, which enables robust spinal EM2 analgesia to emerge. Aim 3 tests the hypothesis that spinal cord contains a novel modulatory oligomer comprised of MOR, KOR, Aro (thus locally synthesized estrogens), mERα, mGluR1 and mGluR2/3 that subserves the dynam- ic modulation of spinal EM2 analgesia over the estrous cycle. Aim 3 also tests the hypothesis that variable ac- tivation of mERα (resulting from fluctuating spinal Aro activity, and thus the synthesis of estrogens immediately proximal to mERα) drives reorganization of the predicted oligomer in diestrus vs. proestrus. Aim 4 tests the hypothesis that interventions shown in Aim 1 to restore spinal EM2 analgesia (e.g., blockade of spinal mERα, mGluR1, or phospholipase C) will be antinociceptive in diestrous rats undergoing chronic pain, which should augment the endogenous spinal EM2 system. Conversely, Aim 4 will also test the hypothesis that interventions shown in Aim 2 to eradicate spinal EM2 analgesia (e.g., blockade of spinal mGluR2/3, c-Src) will be pronocicep- tive in proestrous rats experiencing chronic pain. Collectively, proposed research will provide a new paradigm and suggest new molecular targets (e.g., the predicted oligomer, spinal ERα/Aro) for developing novel phar- macotherapies for pain relief that harnesses the powerful endogenous EM2/MOR analgesic system. Therapies that harness endogenous opioids would lessen the need for their exogenous counterparts, thereby circumvent- ing prescription opioid abuse, which has reached epidemic proportions. Additionally, findings will provide in- sight into etiology of chronic pain in women, since dysfunction of the physiological switch from EM2 anal- gesically non-responsive to responsive states is likely to facilitate developing and/or sustaining chronic pain.

发情（月经）周期和强度会影响µ-阿片类药物的疼痛敏感性和镇痛有效性 Ceptor（MOR） - 选择性阿片类药物，例如，我们最近的发现，即女性大鼠在女性大鼠中引起的镇痛 内源性MOR配体内摩态2（EM2）的静脉（I.T.）在Diestrus期间被诅咒 但是强大的，与雌性在雌性期间的雄性相媲美。发现夹紧的spi的分子碱基 NAL EM2镇痛将揭示新的分子靶标，用于抑制，从而利用，从而解决的药物干预措施 内源性EM2镇痛，减轻了处方阿片类药物的使用，从而减少了它们的滥用。组织 标题产生的目的是，脊柱EM2镇痛的阶段性质是由于发情循环的 脊柱MOR，κ阿片受体（Kor），芳香酶（ARO），膜雌激素之间相互作用的可塑性 受体α（MERα），mglurs及其相关信号伴侣。前三个目的侧重于分子。 规范I.T.的LAR组件（及其组织） EM2镇痛。第四个目标调查了翻译 调查结果的关系。 AIM 1检验以下假设：在Diestrus，脊柱MERα-MGLUR1信号传导期间 通过磷脂酶C和β-arrestin，抑制了脊髓EM2镇痛。 AIM 2检验了以下假设 前弹力，MERα和β-arrestin不再与脊柱EM2镇痛有关。 mglur1现在与 MGLUR2/3通过C-SRC发出信号，支持脊椎飞闪磷脂释放，这使稳健的脊髓EM2镇痛 出现。 AIM 3检验了脊髓包含新型调节寡聚的假设 MOR，KOR，ARO（因此局部合成的雌激素），MERα，MGLUR1和MGLUR2/3，该动态 - 在发情循环中脊柱EM2镇痛的IC调节。 AIM 3还检验了可变ac-的假设 MERα的诱变（由脊柱ARO活性波动产生，因此立即合成雌激素 MERα的近端驱动了Diestrus vs. Pro Estrus中预测的低聚物的重组。 AIM 4测试 AIM 1中显示的干预措施以恢复脊柱EM2镇痛的假设（例如，脊柱MERα的桶， MGLUR1或磷脂酶C）将在经历慢性疼痛的偶有大鼠中具有抗伤害感受，应 增强内源性脊髓EM2系统。相反，AIM 4还将测试干预措施的假设 在AIM 2中显示了radiomate脊髓EM2镇痛（例如，脊柱MGLUR2/3，C-SRC桶）将是pronociepicep- 伴有慢性疼痛的阳离大鼠。拟议的研究集体将提供新的范式 并建议新的分子靶标（例如，预测的低聚物，脊柱ERα/ARO）用于发展新型的phar- 减轻疼痛缓解的大量治疗，可利用强大的内源性EM2/MOR镇痛系统。疗法 线束内源性阿片类药物会减少对外源性对应物的需求，从而规避 处方滥用，已达到流行比例。此外，调查结果将提供 - 由于从EM2肛门的身体转变功能障碍以来，女性慢性疼痛的病因 对响应状态的气质无反应可能会促进发展和/或维持慢性疼痛。