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的疼痛。用于止痛的阿片类药物的使用在- 皱纹，几乎没有对持续疼痛的潜在负面后果进行评估。最近的报道是至关重要的 缺乏可控的长期研究来支持慢性阿片类药物治疗的急剧升级 过去十年的痛苦。虽然一个长期的担忧是可能没有好处，但另一个问题是阿片类药物 可能会对疼痛产生负面影响。阿片类药物治疗对促进- 在阿片类药物停药后很长时间的疼痛过程。如本提案所述，阿片类药物诱导的强健时间- 疼痛确实发生了，这使这一现象成为一个至关重要的理解现象。 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： 短程吗啡(5 mg/kg，b.i.d。5-7天)可以放大 此后数月的神经病理性疼痛。引人注目的是，这种有害的阿片类药物效应在所有测试的模型中都会发生 到目前为止：炎症性疼痛，周围和中枢神经病理性疼痛，以及手术后疼痛，支持 这是一个值得研究的普遍现象。吗啡的这种意想不到的跨越时间和死亡的影响- Verse疼痛模型此前未见报道。除了我们最初的研究外，目前还没有关于- 对这种多月来神经性疼痛的夸大的脊椎机械基础进行了验证 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 在免疫和神经胶质功能、神经病理性疼痛以及对阿片类药物的反应方面的差异，表明不同的非阿片类药物。 很可能会在不同的性别中找到可笑的机制。第一个目标是研究短程吗啡是如何 在创伤后早期，功能性地改变同侧腰椎背侧SPI的神经免疫学- Nal脊髓，并发现这些变化中的哪一个介导了疼痛的增强。第二个目标是利用状态 脊髓中最先进的健壮活动标记(RAM)技术，以解决如何识别更多的介质- 吗啡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 州政府。第三个目的是研究脊髓上促进吗啡诱导的神经元时序化的机制。 玫瑰花样的疼痛。目的3利用最先进的DREADD可逆灭活小胶质细胞与兴奋性神经元 为了确定尾侧颗粒岛叶皮质(CGIC)的作用，我们以前已经展示过(在ab- 创伤后早期吗啡的感觉)对慢性疼痛的维持至关重要。在这里我们将可逆地抑制， 以细胞型靶向方式，CGIC内的小胶质细胞或兴奋性神经元要么仅在吗啡戒断期间- 是否仅在吗啡诱导的疼痛慢性化期间确定CGIC参与了诱导 而不是维持这种增强的神经病理性疼痛状态。

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.