Enduring enhancement of neuropathic pain by early post-trauma morphine

项目摘要 阿片类药物被广泛用于治疗创伤后疼痛。阿片类药物用于疼痛管理已经显着地- 折痕，很少评估持续疼痛的潜在负面后果。最近的报告显示 缺乏对照的长期研究来支持阿片类药物治疗慢性 过去十年的痛苦。虽然一个长期的担忧是可能没有好处，另一个是阿片类药物 可能会对疼痛产生负面影响。阿片类药物治疗对亲- 阿片类药物停药后疼痛持续时间长。如该提案所述，稳健的阿片类药物诱导的慢性- 疼痛确实会发生，这是一个需要理解的关键现象。 令人不安的是，我们发现在创伤前后给予阿片类药物可能是禁忌的： 用吗啡（5 mg/kg b.i.d. 5-7天）可以放大的幅度和持续时间 神经性疼痛数月后。引人注目的是，这种有害的阿片类药物作用发生在所有测试的模型中 迄今为止：炎性疼痛，外周和中枢神经性疼痛，以及术后疼痛， 这是一个值得研究的普遍现象。吗啡的这种意想不到的作用随着时间的推移和剂量的增加- 以往没有关于垂直疼痛模型的报道。除了我们的初步研究，没有什么是已知的，关于- 通过一个神经病理性疼痛的多个月夸大的脊髓机制基础， 短暂接触吗啡仅限于创伤后早期。 提出了三个目标。所有研究都是在两性中进行的，因为有记录的男性/女性 免疫和神经胶质功能、神经性疼痛和对阿片类药物反应的差异表明， 出轨的机制很可能会在两性之间找到。第一个目标是研究短期吗啡 在创伤后早期，在功能上改变了同侧腰椎背侧脊髓的神经免疫学， 并发现这些变化介导疼痛增强。第二个目标是利用国家的， 最先进的脊髓稳健活动标记（RAM）技术，以解决如何识别莫尔的介质， 吗啡引起的疼痛增强与具有确定激活的逆行标记脊髓丘脑神经元一致 状态第三个目的是研究脊髓上的机制，有助于吗啡诱导的慢性化的神经， 性疼痛目的3利用最先进的DREADD可逆性灭活小胶质细胞与兴奋性神经元 为了定义尾侧颗粒岛叶皮质（CGIC）的作用，我们之前已经显示（在ab中）， 早期创伤后吗啡的感觉）对慢性疼痛维持至关重要。在这里，我们将可逆地抑制， 在细胞类型靶向的方式，无论是小胶质细胞或兴奋性神经元在CGIC或仅在吗啡剂量， 或仅在吗啡诱导的疼痛慢性化期间确定CGIC参与诱导 与维持这种增强的神经性疼痛状态相比。

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.