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在人造光(LAN)中。 尽管最初的假设是无害的，但暴露在局域网中会扰乱昼夜节律，并与 几种临床疾病的患病率增加。这种所谓的光污染开始于一次深度 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 表明暴露在局域网中会扰乱昼夜节律，显著增加外周和中枢 炎症，并提高小鼠的疼痛反应。疼痛是高医疗费用的一个重要原因， 丧失生产力，以及一条通向鸦片成瘾的常见途径。目前，几乎没有最佳的治疗方法。 慢性疼痛和潜在原因，以及导致个人从治疗使用到 阿片类药物滥用仍未指明。疼痛反应表现出每日变化，反应在 晚上好。我们假设，由于暴露在局域网中，扰乱了昼夜节律，从而导致炎症 并影响疼痛反应。我们将检验这一假设，并预测暴露于 夜间昏暗的灯光(DLan)会表现出疼痛反应的增强。我们进一步假设昼夜节律 对阿片类药物治疗疼痛的反应在夜间会受到光线的干扰。因此，我们预测较高剂量的 在暴露于昏暗光线下的动物中，需要多种阿片类药物才能获得类似的疼痛反应抑制 晚上好。这些假设将在两个具体目标上得到检验。在第一个具体目标中，我们将描述 Dlan暴露对小鼠疼痛反应的影响。因为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。昼夜节律受光与表达黑素的视网膜神经节细胞相互作用的影响 它们主要对短波长(蓝色)光敏感，而对长波长光相对不敏感 波长(红色)光。因此，我们将检查在黑暗、暗白、昏暗中暴露后的疼痛反应。 蓝色或暗淡的红光，以测试暴露在dLan中的波长是否由 影响昼夜节律的时钟夹带(白色和蓝色)会提高疼痛反应，而暴露在 黑夜或夜间暗淡的红光可防止疼痛反应增强。《特定目标2》将测试 DLan暴露扰乱昼夜节律改变敏感性的假说 对鸦片类药物的反应性。我们预测，对鸦片类药物的剂量反应将发生变化，因此增加的鸦片类药物 将需要剂量来抑制疼痛反应。综上所述，该项目的成果将填补 在对昼夜节律在疼痛反应和疼痛治疗中的作用的认识上存在重要差距。如果我们的 假设没有被证明是错误的，那么这些结果可以很容易地和廉价地转换到个人身上 忍受着痛苦--例如，蓝光遮挡护目镜或其他环境照明调整--来对准 昼夜节律，以改善疼痛治疗结果，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.