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

发情（月经）周期和雌激素影响μ-阿片受体（莫尔）选择性阿片类药物的疼痛敏感性和镇痛效果，例如，我们最近的发现表明，雌性大鼠鞘内（i.t.）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。揭示脊髓EM 2阻滞镇痛的分子基础将揭示药物干预的新分子靶点， 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。前三个目标集中在调节i.t.的分子成分（及其组织）上。EM 2镇痛。第四个目标是研究翻译的相关性。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，其在动情周期中支持脊髓EM 2镇痛的动态调节。目的3还验证了mERα的可变激活（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，脊髓mGluR 2/3，c-Src的阻断）将在经历慢性疼痛的发情前期大鼠中具有亲伤害感受性。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）用于开发利用强大的内源性EM 2/莫尔镇痛系统的新型镇痛药物疗法。疗法 利用内源性类阿片将减少对外源性类阿片的需求，从而避免已达到流行病程度的处方类阿片滥用。此外，研究结果将提供深入了解女性慢性疼痛的病因，因为从EM 2镇痛无反应到反应状态的生理开关功能障碍可能会促进慢性疼痛的发展和/或持续。

Estrous (menstrual) cycle and estrogens influence pain sensitivity and analgesic effectiveness of µ-opioid receptor (MOR)-selective opioids, e.g., our recent finding that the analgesia elicited in female rats by the intrathecal (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 spinal 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 molecular components (and their organization) that regulate i.t. EM2 analgesia. The fourth aim investigates translational 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 dynamic modulation of spinal EM2 analgesia over the estrous cycle. Aim 3 also tests the hypothesis that variable activation 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 pronociceptive 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 pharmacotherapies 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 circumventing prescription opioid abuse, which has reached epidemic proportions. Additionally, findings will provide insight into etiology of chronic pain in women, since dysfunction of the physiological switch from EM2 analgesically non-responsive to responsive states is likely to facilitate developing and/or sustaining chronic pain.