Division of Biosciences, The Ohio State University College of Dentistry, USA.
Division of Biosciences, The Ohio State University College of Dentistry, USA; Department of Neuroscience, The Ohio State University Wexner Medical Center, USA.
Brain Behav Immun. 2018 Mar;69:113-123. doi: 10.1016/j.bbi.2017.11.005. Epub 2017 Nov 8.
Mounting evidence indicates that stress influences the experience of pain. Exposure to psychosocial stress disrupts bi-directional communication pathways between the central nervous system and peripheral immune system, and can exacerbate the frequency and severity of pain experienced by stressed subjects. Repeated social defeat (RSD) is a murine model of psychosocial stress that recapitulates the immune and behavioral responses to stress observed in humans, including activation of stress-reactive neurocircuitry and increased pro-inflammatory cytokine production. It is unclear, however, how these stress-induced neuroimmune responses contribute to increased pain sensitivity in mice exposed to RSD. Here we used a technique of regional analgesia with local anesthetics in mice to block the development of mechanical allodynia during RSD. We next investigated the degree to which pain blockade altered stress-induced neuroimmune activation and depressive-like behavior.
Following development of a mouse model of regional analgesia with discrete sensory blockade over the dorsal-caudal aspect of the spine, C57BL/6 mice were divided into experimental groups and treated with Ropivacaine (0.08%), Liposomal Bupivacaine (0.08%), or Vehicle (0.9% NaCl) prior to exposure to stress. This specific region was selected for analgesia because it is the most frequent location for aggression-associated pain due to biting during RSD. Mechanical allodynia was assessed 12 h after the first, third, and sixth day of RSD after resolution of the sensory blockade. In a separate experiment, social avoidance behavior was determined after the sixth day of RSD. Blood, bone marrow, brain, and spinal cord were collected for immunological analyses after the last day of RSD in both experiments following behavioral assessments.
RSD increased mechanical allodynia in an exposure-dependent manner that persisted for at least one week following cessation of the stressor. Mice treated with either Ropivacaine or Liposomal Bupivacaine did not develop mechanical allodynia following exposure to stress, but did develop social avoidance behavior. Neither drug affected stress-induced activation of monocytes in the bone marrow, blood, or brain. Neuroinflammatory responses developed in all treatment groups, as evidenced by elevated IL-1β mRNA levels in the brain and spinal cord after RSD.
In this study, psychosocial stress was associated with increased pain sensitivity in mice. Development of mechanical allodynia with RSD was blocked by regional analgesia with local anesthetics, Ropivacaine or Liposomal Bupivacaine. Despite blocking mechanical allodynia, these anesthetic interventions did not prevent neuroimmune activation or social avoidance associated with RSD. These data suggest that stress-induced neuroinflammatory changes are not associated with increased sensitivity to pain following RSD. Thus, blocking peripheral nociception was effective in inhibiting enhanced pain signaling without altering stress-induced immune or behavioral responses.
越来越多的证据表明，压力会影响疼痛的体验。暴露于心理社会压力会破坏中枢神经系统和外周免疫系统之间的双向交流途径，并可能使受压受试者的疼痛频率和严重程度恶化。反复社会挫败（RSD）是一种心理社会压力的小鼠模型，它再现了人类观察到的对压力的免疫和行为反应，包括应激反应性神经回路的激活和促炎细胞因子产生的增加。然而，尚不清楚这些应激引起的神经免疫反应如何导致 RSD 暴露的小鼠疼痛敏感性增加。在这里，我们使用在小鼠中使用局部麻醉剂进行区域镇痛的技术来阻断 RSD 期间机械性痛觉过敏的发展。接下来，我们研究了疼痛阻断在多大程度上改变了应激诱导的神经免疫激活和抑郁样行为。
在使用局部麻醉剂在脊柱背侧-尾侧区域进行小鼠区域镇痛模型的发展之后，将 C57BL/6 小鼠分为实验组，并在暴露于应激之前用罗哌卡因（0.08%）、脂质体布比卡因（0.08%）或载体（0.9%NaCl）进行处理。选择该特定区域进行镇痛是因为它是由于 RSD 期间咬伤而导致攻击相关疼痛最常见的位置。在 RSD 后的第一天、第三天和第六天，在感觉阻滞消退后，评估机械性痛觉过敏。在单独的实验中，在 RSD 的第六天后确定社交回避行为。在两个实验的最后一天进行行为评估后，收集血液、骨髓、大脑和脊髓进行免疫分析。
RSD 以暴露依赖性方式增加机械性痛觉过敏，在应激停止后至少持续一周。用罗哌卡因或脂质体布比卡因治疗的小鼠在暴露于应激后不会发生机械性痛觉过敏，但会发生社交回避行为。两种药物均未影响应激诱导的骨髓、血液或大脑中单核细胞的激活。在所有治疗组中均发生了神经炎症反应，这表现在 RSD 后大脑和脊髓中 IL-1β mRNA 水平升高。
在这项研究中，心理社会压力与小鼠疼痛敏感性增加有关。用局部麻醉剂罗哌卡因或脂质体布比卡因进行区域镇痛可阻断 RSD 引起的机械性痛觉过敏。尽管阻断了机械性痛觉过敏，但这些麻醉干预并不能预防 RSD 相关的神经免疫激活或社交回避。这些数据表明，应激诱导的神经炎症变化与 RSD 后疼痛敏感性增加无关。因此，阻断外周伤害感受可有效抑制增强的疼痛信号传导，而不改变应激诱导的免疫或行为反应。
