Enduring enhancement of neuropathic pain by early post-trauma morphine

创伤后早期吗啡持久增强神经性疼痛

• 批准号: 9906887
• 负责人: LINDA WATKINS
• 金额: $ 53.04万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906887
• 关键词: Address; Anatomy; Animal Model; Anti-Inflammatory Agents; Antioxidants; Brain; Dorsal; Exposure to; Female; Immune; Inflammation Mediators; Inflammatory; Ipsilateral; Label; Longitudinal Studies; Lumbar spinal cord structure; Maintenance; Mediating; Mediator of activation protein; Microglia; Modeling; Morphine; Neurons; Neuropathy; Opioid; Pain; Pain management; Peripheral; Persistent pain; Pharmacological Treatment; Postoperative Pain; Postoperative Period; Reporting; Role; Spinal; Spinal Cord; Study models; System; Technology; Testing; Time; Trauma; base; cell type; chronic pain; cytokine; designer receptors exclusively activated by designer drugs; dorsal horn; excitatory neuron; in vivo; inflammatory pain; male; neuroimmunology; neuroinflammation; neuronal cell body; neuronal excitability; novel; opioid use; pain model; painful neuropathy; post-trauma; prevent; response; sex

Project Summary Opioids are widely used to treat pain after trauma. Opioid use for pain management has dramatically in- creased, with little assessment of potential negative consequences for ongoing pain. Recent reports are critical of the lack of controlled, long-term studies to support the dramatic escalation of opioid treatment for chronic pain over the past decade. While one long-term concern is that there may be no benefit, another is that opioids could have negative consequences for pain. There would be major implications were opioid treatment to pro- long the course of pain long after opioid cessation. As described in this proposal, robust opioid-induced chroni- fication of pain does indeed occur, making this a phenomenon critical to understand. Disturbingly, we have discovered that opioids given around the time of trauma may be contraindicated: a brief course of treatment with morphine (5 mg/kg b.i.d. for 5-7 days) can amplify the magnitude and duration of neuropathic pain for months thereafter. Strikingly, this deleterious opioid effect occurs across all models tested to date: inflammatory pain, peripheral and central neuropathic pain, and post-operative pain, supportive that this is a widespread phenomenon worthy of study. This unanticipated effect of morphine across time and di- verse pain models had not been previously reported. Beyond our initial studies, nothing is known regard- ing the spinal mechanistic underpinnings of this multi-month exaggeration of neuropathic pain by a brief exposure to morphine restricted to the early post-trauma period. Three Aims are proposed. All studies are undertaken in both sexes, given that documented male/female differences in immune and glial function, neuropathic pain, and responses to opioids, suggest that distinct un- derlying mechanisms will likely be found across sexes. The first Aim examines how a short course of morphine in the early post-trauma period functionally modifies the neuroimmunology of the ipsilateral lumbar dorsal spi- nal cord and discovers which of these changes mediate pain enhancement. The second Aim utilizes state-of- the-art Robust Activity Marking (RAM) technologies in spinal cord to address how identified mediators of mor- phine-induced pain enhancement align with retrogradely labeled spinothalamic neurons with defined activation state. The third Aim examines supraspinal mechanisms contributing to morphine-induced chronification of neu- ropathic pain. Aim 3 utilizes state-of-the-art DREADD reversible inactivation of microglia vs. excitatory neurons to define the role of the caudal granular insular cortex (CGIC), which we have previously shown (in the ab- sence of early post-trauma morphine) to be critical to chronic pain maintenance. Here we will reversibly inhibit, in a cell-type targeted fashion, either microglia or excitatory neurons in CGIC either only during morphine dos- ing or only during the period of morphine-induced chronification of pain to define CGIC involvement in induction versus maintenance of this enhanced neuropathic pain state.

项目概要 阿片类药物广泛用于治疗创伤后疼痛。阿片类药物用于疼痛管理已取得显着进展 皱纹，很少评估持续疼痛的潜在负面后果。最近的报告至关重要 缺乏受控的长期研究来支持阿片类药物治疗慢性病的急剧升级 过去十年的痛苦。虽然一个长期的担忧是可能没有任何好处，但另一个担忧是阿片类药物 可能会对疼痛产生负面影响。阿片类药物治疗将产生重大影响 停用阿片类药物后疼痛持续时间较长。正如该提案中所述，阿片类药物引起的慢性慢性 疼痛确实存在，因此理解这一现象至关重要。 令人不安的是，我们发现在创伤期间给予阿片类药物可能是禁忌的： 短期吗啡疗程（5 毫克/公斤，每日两次，持续 5-7 天）可增强吗啡的严重程度和持续时间 此后数月出现神经性疼痛。引人注目的是，这种有害的阿片类药物效应出现在所有测试的模型中 迄今为止：炎症性疼痛、周围和中枢神经性疼痛以及术后疼痛，支持 这是一个普遍存在的现象，值得研究。吗啡这种意想不到的跨时间和跨时间效应 此前尚未报道过反向疼痛模型。除了我们最初的研究之外，我们一无所知—— 神经病理性疼痛持续数月被夸大的脊柱机制基础 短期接触吗啡仅限于创伤后早期。 提出了三个目标。鉴于有记录的男性/女性，所有研究均在两性中进行 免疫和神经胶质功能、神经性疼痛以及对阿片类药物反应的差异表明，不同的非 不同性别的人都可能会发现死亡机制。第一个目标探讨短期吗啡疗程如何 在创伤后早期，功能性地改变同侧腰椎背侧脊髓的神经免疫学 神经索并发现这些变化中哪些会介导疼痛增强。第二个目标利用state-of- 脊髓中最先进的鲁棒活动标记（RAM）技术可解决如何识别莫 碱诱导的疼痛增强与具有明确激活的逆行标记的脊髓丘脑神经元相一致 状态。第三个目标是检查吗啡诱导的神经细胞慢性化的脊髓上机制 病理性疼痛。目标 3 利用最先进的 DREADD 可逆性抑制小胶质细胞与兴奋性神经元的失活 定义尾粒岛叶皮质（CGIC）的作用，我们之前已经展示过（在ab- 创伤后早期吗啡的感觉）对于维持慢性疼痛至关重要。在这里我们将可逆地抑制， 以细胞类型靶向方式，CGIC 中的小胶质细胞或兴奋性神经元仅在吗啡剂量期间 或仅在吗啡诱导的慢性疼痛期间定义 CGIC 参与诱导 与维持这种增强的神经性疼痛状态相比。