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.

动情（月经）周期和雌激素影响疼痛敏感性和μ-阿片受体的镇痛效果。 受体（莫尔）-选择性阿片样物质，例如，我们最近的发现是，在雌性大鼠中， 经皮给药内源性莫尔配体内吗啡肽2（EM 2）的应用在动情间期受到抑制 但健壮且与发情前期的雄性相当。揭示了钳位螺旋体的分子基础- 最终的EM 2镇痛将揭示药物干预的新分子靶点，这些药物干预可以解除抑制，从而利用， 内源性EM 2镇痛，减少处方阿片类药物的使用，从而减少其滥用。组委会 目的是，脊髓EM 2镇痛在动情周期的阶段性本质是由 脊髓莫尔、κ-阿片受体（KOR）、芳香化酶（Aro）、膜雌激素之间相互作用的可塑性 受体α（mERα）、mGluRs及其相关信号传导伴侣。前三个目标集中在分子上， 管理信息技术的较大组件（及其组织）EM 2镇痛。第四个目的是研究transla- 调查结果的相关性。目的1验证在动情间期，脊髓mERα-mGluR 1信号转导， 通过磷脂酶C和β-抑制蛋白，抑制脊髓EM 2镇痛。目标2检验假设， 动情前期，mERα和β-arrestin不再与脊髓EM 2镇痛相关; mGluR 1现在与 mGluR 2/3通过c-Src发出信号，促进脊髓强啡肽释放，从而实现强大的脊髓EM 2镇痛 出现。目的3检验脊髓含有一种新的调节寡聚体的假设， 莫尔，KOR，Aro（因此局部合成的雌激素），mERα，mGluR 1和mGluR 2/3，它们有助于动力学。 在动情周期中脊髓EM 2镇痛的ic调节。目标3还检验了变量ac的假设。 mERα激活（由波动的脊髓Aro活性引起，因此立即合成雌激素） mERα近端）驱动间情期与发情前期预测寡聚体的重组。目标4测试 假设目标1中所示的恢复脊髓EM 2镇痛的干预（例如，阻断脊髓mERα， mGluR 1，或磷脂酶C）在经历慢性疼痛的去情大鼠中具有抗伤害感受作用， 增强内源性脊髓EM 2系统。相反，目标4也将检验干预措施 如目的2所示，以根除脊髓EM 2镇痛（例如，阻断脊髓mGluR 2/3，c-Src）将是普罗诺西普- 在经历慢性疼痛的发情前期大鼠中有效。总的来说，拟议的研究将提供一个新的范例， 并提出新的分子靶点（例如，预测的寡聚体，脊髓ERα/Aro）用于开发新的phar- 利用强大的内源性EM 2/莫尔镇痛系统缓解疼痛的macotherapies。疗法 利用内源性阿片类药物将减少对外源性阿片类药物的需求，从而避免- 处方阿片类药物滥用，已达到流行病的比例。此外，调查结果将提供- 视线进入病因的慢性疼痛的妇女，因为功能障碍的生理开关从EM 2肛门， 对响应状态的姿势无响应可能促进慢性疼痛的发展和/或持续。