Effects of Light at Night and Disrupted Circadian Rhythms on Pain

摘要 电照明的广泛采用导致了夜间大量暴露于人造光（LAN）。 虽然最初认为无害，但暴露于LAN会扰乱昼夜节律，并与 几种临床疾病的患病率增加。这种所谓的光污染始于一个深 认识到昼夜节律对典型的适应性功能的重要性。我们的初步数据 表明暴露于LAN会扰乱昼夜节律，显著增加外周和中枢神经系统 炎症，并提高小鼠的疼痛反应性。疼痛是导致高医疗费用的重要原因， 丧失生产力，以及鸦片成瘾的常见途径。目前，几乎没有最佳治疗方法， 慢性疼痛和根本原因，以及导致个体从治疗性使用到 阿片剂滥用情况仍然不明。疼痛反应性显示每日变化， 晚上我们假设，由于暴露于LAN而引起的昼夜节律紊乱， 过程和影响疼痛反应。我们将测试这一假设，并预测小鼠暴露于 夜间昏暗灯光（dLAN）将显示升高的疼痛反应性。我们进一步假设昼夜节律 对阿片类药物止痛的反应会被夜间的光线扰乱。因此，我们预测， 在暴露于昏暗光线下的动物中， 晚上这些假设将在两个具体目标中得到检验。在第一个具体目标中，我们将描述 dLAN暴露对小鼠疼痛反应性的影响。由于众所周知的性别差异， 疼痛反应，我们将测试雄性和雌性小鼠在暴露于 dLAN。光与表达黑视蛋白的视网膜神经节细胞相互作用， 其主要对短波长（蓝色）光响应，而对长波长（蓝色）光相对不响应。 波长（红色）光。因此，我们将检查暴露于黑暗、昏暗白色、昏暗 蓝色或昏暗的红光，以测试暴露于dLAN的波长， 影响生物钟的夹带（白色和蓝色）将提高疼痛反应性，而暴露于 夜间黑暗或昏暗的红光可防止疼痛反应性升高。具体目标2将测试 假设暴露于dLAN会破坏昼夜节律组织， 对鸦片的反应。我们预测，阿片类药物的剂量反应将发生变化， 需要抑制疼痛反应的剂量。总的来说，这个项目的结果将填补一个 关于昼夜节律在疼痛反应和疼痛治疗中的作用的知识存在重要差距。如果我们的 假设没有被推翻，那么这些结果就可以很容易地和廉价地转化为个人 遭受疼痛-例如，蓝光阻挡护目镜或其他环境照明调节-以对准 昼夜节律，以改善疼痛治疗结果，并避免阿片类药物滥用。

Abstract Widespread adoption of electric lighting has led to significant exposure to artificial light at night (LAN). Although initially assumed innocuous, exposure to LAN disrupts circadian rhythms and is correlated with increased prevalence of several clinical disorders. This so-called light pollution began prior to a deep appreciation of the importance of circadian rhythms to typical, adaptive functioning. Our preliminary data indicate that exposure to LAN disrupts circadian rhythms, dramatically increases peripheral and central inflammation, and elevates pain responsiveness in mice. Pain is a significant cause of high medical costs, lost productivity, and a common pathway to opiate addiction. Currently, there are few optimal treatments for chronic pain and the underlying causes, and predictive factors that lead individuals from therapeutic use to opiate abuse remain unspecified. Pain responsiveness shows daily variation with elevated responses at night. We hypothesize that disrupted circadian rhythms, caused by exposure to LAN, drive inflammatory processes and influence pain responsiveness. We will test this hypothesis and predict that mice exposed to dim light at night (dLAN) will display elevated pain responsiveness. We further hypothesize that circadian responses to opiate management of pain are deranged by light at night. Thus, we predict that higher doses of opiates are required to obtain similar suppression of pain responses in animals exposed to dim light at night. These hypotheses will be tested in two specific aims. In the first specific aim, we will characterize the effects of dLAN exposure on pain responsiveness in mice. Because of the well-known sex differences in pain responsiveness, we will test both male and female mice in pain responsiveness after exposure to dLAN. Circadian clocks are entrained by light interacting with melanopsin-expressing retinal ganglion cells which are primarily responsive to short-wavelength (blue) light, and relatively unresponsive to long wavelength (red) light. Thus, we will examine pain responsiveness after exposure to dark, dim white, dim blue, or dim red light at night to test the hypothesis that exposure to dLAN comprised of wavelengths that affect circadian clock entrainment (white and blue) will elevate pain responsiveness, whereas exposure to dark nights or dim red light at night prevents elevated pain responsiveness. Specific Aim 2 will test the hypothesis that disruption of circadian organization by exposure to dLAN changes sensitivity/ responsiveness to opiates. We predict that dose responses to opiates will shift so that increased opiate dosages will be required to suppress pain responses. Taken together, the results of this project will fill an important gap in knowledge about the role of circadian rhythms in pain responses and pain treatment. If our hypotheses are not disproved, then these results could easily and inexpensively be translated to individuals suffering from pain—e.g., blue-light blocking goggles or other environmental lighting adjustments—to align circadian rhythms, to improve pain treatment outcomes, and avoid opiate abuse.