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

动情(月经)周期和雌激素影响µ-阿片受体(MOR)选择性阿片类药物的疼痛敏感性和镇痛效果，例如我们最近发现鞘内注射(I.T.)对雌性大鼠的镇痛作用。内源性MOR配体内吗啡2(EM2)的应用在发情间期受到抑制 但体格健壮，可与发情前期的雄性相提并论。揭示钳制脊髓EM2止痛的分子基础将为药物干预提供新的分子靶点，从而解除抑制，从而控制， 内源性EM2止痛，减少处方阿片类药物的使用，从而减少其滥用。组织工作 产生目的的准则是，动情周期中脊髓EM2止痛的阶段性结果是 脊髓MOR、κ阿片受体、芳香酶、膜雌激素相互作用的可塑性 受体α(Merα)、mGluRs及其相关的信号伙伴。前三个目标集中在管理信息技术的分子成分(及其组织)上。EM2镇痛。第四个目的是研究研究结果的翻译关联性。目的1验证以下假设：在发情间期，脊髓聚合体α-mGluR1信号转导， 通过磷脂酶C和β−arrestin，抑制脊髓EM2的镇痛作用。Aim 2测试了假设，在 动情前期、merα和β−arrestin不再与脊髓EM2止痛相关；mGluR1现在与 MGluR2/3通过c-Src发出信号，促进脊髓强啡肽的释放，从而实现强大的脊髓EM2镇痛 才能出现。AIM 3验证了脊髓含有一种新的调节性寡聚体的假设，该寡聚体包括 MOR、KOR、ARO(局部合成的雌激素)、Merα、mGluR1和mGluR2/3参与了动情周期脊髓EM2镇痛的动态调节。Aim 3还测试了一种假设，即可变激活的merα(由脊髓Aro活性波动引起，从而立即合成雌激素 Merα近端)推动发情间期与发情前期预测的寡聚体的重组。AIM 4测试 假设目标1中所示的干预措施可恢复脊髓EM2止痛(例如，阻断脊髓聚合体α， MGluR1，或磷脂酶C)对经历慢性疼痛的发情大鼠具有抗伤害性作用，这应该是 增强内源性脊髓EM2系统。相反，目标4也将检验干预措施 在目标2中显示的根除脊髓EM2止痛(例如，阻断脊髓mGluR2/3，c-Src)将在经历慢性疼痛的发情前期大鼠中产生致痛作用。总的来说，拟议的研究将提供一种新的范式 并提出了新的分子靶点(例如，预测的寡聚体，脊髓ERα/Aro)，用于开发利用强大的内源性EM2/MOR止痛系统的新型止痛药物疗法。治疗方法 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，因为处方类阿片类药物滥用已经达到流行的程度。此外，这些发现将为女性慢性疼痛的病因提供洞察力，因为从EM2麻醉无反应状态到反应状态的生理开关功能障碍可能有助于慢性疼痛的发展和/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.