Fibromyalgia and melatonin: are they related?
Fibromyalgia and melatonin: are they related?
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纤维肌痛和褪黑激素：它们有关系吗？
DOI：
10.1046/j.1365-2265.1998.00548.x
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发表时间：
1998
影响因子：
3.2
通讯作者：
S. Webb
中科院分区：
文献类型：
--
作者：
S. Webb
纤维肌痛综合征（FMS）是一种常见的风湿性疾病，影响高达1%的一般人群（Doherty & Jones，1995）。其发病机制似乎是功能性的，而不是病理性的，因为没有明显的炎症，代谢或结构异常的研究证据可以证明。纤维肌痛的主要症状是特定压痛部位的慢性疼痛，通常伴有全身僵硬，最小用力后极度疲劳，以及非恢复性睡眠，因此患者醒来时精神不振;此类患者无法集中注意力，易怒和易出汗，并可能患有头痛，弥漫性腹痛，排便习惯多变和尿频。主要的松果体激素褪黑激素是在夜间暴露于黑暗中时分泌的。关于环境光的信息：暗周期通过多突触神经通路到达松果体，该通路从视网膜延伸，通过下丘脑和脊髓，到达交感上级颈神经节，突触后纤维从该颈神经节到达松果体细胞。在黑暗中，这些突触后纤维的b-肾上腺素能刺激决定褪黑激素的合成和分泌。在这篇文章中，Wikneret等人（1998）描述了与健康对照组相比，FMS女性的夜间峰值较低，褪黑激素分泌减少。功能性风湿病与松果体的神经内分泌功能紊乱有什么关系？这项工作所基于的最初假设认为，由于FMS患者有睡眠问题，并且已知褪黑激素促进睡眠，因此睡眠障碍可能与循环褪黑激素降低有关，事实确实如此。然而，可能的因果关系的方向尚不清楚。让我们回顾现有的证据可能与松果体功能FMS。5-羟色胺是松果体细胞中褪黑激素的前体，由色氨酸合成，色氨酸被认为在FMS中从肠道吸收不良（Moldofsky，1994）。这与FMS中血清素抗体的存在一起，将产生可用血清素池的减少。前脑5-羟色胺水平低与失眠有关，给予前体5-羟基色氨酸可逆转失眠（Neeck & Riedel，1994）。投射到脊髓的胆碱能通路的激活抑制背角神经元中各种伤害性刺激的信号传递（Neeck & Riedel，1994）。与这一假设一致，在FMS患者中观察到循环色氨酸与疼痛之间的反比关系（Moldofsky，1994），以及循环5-羟色胺浓度的降低，血小板5-羟色胺结合位点数量的伴随增加，推测在这种风湿综合征中脑5-羟色胺可用性也降低。因此，FMS中色氨酸的吸收减少和随之而来的可用5-羟色胺的减少可能是导致褪黑激素合成减少、睡眠模式异常和FMS典型疼痛的原因。此外，其他可能的联系也值得考虑。松果体在其功能中表现出昼夜节律、日内节律和日外节律，这决定了许多动物物种对环境的日常和季节性适应。在城市化的人类中，这些时间生物学特征并不那么明显，尽管有数据表明在极端情况下存在季节性和日常节奏的变化（Webb & Puig-Domingo，1995）。健康受试者在早晨和傍晚醒来后处于最佳状态，而FMS受试者在醒来后感觉很糟糕，傍晚时精疲力竭，仅在中午前后报告一个相对健康的时间间隔。此外，一些FMS患者报告了明显的季节性症状变化，冬季症状加重（Moldofsky，1994），这是安排和评价治疗反应时需要考虑的一个因素。由于睡眠障碍被认为是大多数FMS其他症状的核心，治疗的目的应该是促进宁静的睡眠，同时考虑到所涉及的时间生物学特征。松果体是否参与这些时间生物学差异尚不清楚，但值得进一步关注（Moldofsky，1994）。另一方面，已提出FMS中存在全身性神经植物性疾病，这也可能是由于减少的肾上腺素能刺激导致褪黑激素合成减少的原因。此外，中枢或外周神经系统或两者在FMS永久化的起始中发挥作用的程度目前尚不清楚。从神经内分泌的角度来看，FMS有一系列特征性特征，如高泌乳素血症、内啡肽和脑啡肽升高、TSH和T4低至正常伴T3降低（如在"病态甲状腺功能正常综合征"中观察到的），以及循环皮质醇正常至高伴地塞米松治疗后不完全抑制。
Fibromyalgia syndrome (FMS) is a common rheumatic disease which affects up to 1% of the general population (Doherty & Jones, 1995). Its pathogenesis appears to be functional rather than pathological, since no investigational evidence of overt inflammatory, metabolic or structural abnormality can be demonstrated. The principal symptoms of fibromyalgia are chronic pain at specific tender sites, often associated with generalised stiffness, extreme fatigability after minimal exertion, and non-restorative sleep so patients awake unrefreshed; such patients cannot concentrate, are irritable and weepy, and may suffer from headache, diffuse abdominal pain, variable bowel habit and urinary frequency. The main pineal hormone melatonin is secreted at night during exposure to darkness. Information on the environmental light:dark cycle reaches the pineal through a multisynaptic neural pathway which extends from the retina, through the hypothalmaus and spinal cord, to the sympathetic superior cervical ganglia from which the postsynaptic fibers reach the pinealocytes. During darkness b-adrenergic stimulation by these postsynaptic fibers determine melatonin synthesis and secretion. In this issue Wikneret al. (1998) describe a lower nocturnal peak and a decreased secretion of melatonin in women with FMS when compared with healthy matched controls. How can a functional rheumatic disease be related to a neuroendocrine dysfunction of the pineal gland? The initial hypothesis on which this work was based considered that since patients with FMS had sleeping problems and melatonin is known to promote sleep, the sleep disturbance might be related to lower circulating melatonin, as indeed was the case. However, the direction of a possible cause-effect relationship is unclear. Let us review the evidence available which may relate pineal function with FMS. Serotonin, a precursor of melatonin in the pinealocyte, is synthesized from trytophan, which is thought to be defectively absorbed from the gut in FMS (Moldofsky, 1994). This together with the presence of serotonin antibodies in FMS, would produce a reduction in the available pool of serotonin. Low forebrain serotonin is associated with insomnia which is reversed by administering the precursor 5-hydroxy-tryptophan (Neeck & Riedel, 1994). Activation of the serotoninergic pathway projecting to the spinal cord suppresses signal transmission of various noxious stimuli in dorsal horn neurons (Neeck & Riedel, 1994). In concordance with this hypothesis, an inverse relationship between circulating tryptophan and pain in FMS patients has been observed (Moldofsky, 1994), as well as a reduction in the circulating serotonin concentration, a concomitant increase in the number of platelet serotonin binding sites and presumably also a reduced brain serotonin availability in this rheumatic syndrome. So, the reduced absorption of tryptophan in FMS and consequent decrease of available serotonin could be responsible for reduced melatonin synthesis, abnormal sleep pattern and pain typical of FMS. Additionally, other possible connections deserve consideration. The pineal exhibits diurnal, infradian and ultradian rhythms in its function, which determine daily and seasonal adaptations to the environment in many animal species. In urbanized humans these chronobiological features are not so evident, even though there are data which suggest the existence of variations of seasonal and daily rhythms in extreme situations (Webb & Puig-Domingo, 1995). Diurnal changes in well-being differ considerably in healthy subjects – who are at their best after waking in the morning and in the early evening – and FMS, who only report one interval of relative well-being around midday after feeling awful on waking and exhausted by early evening. Furthermore, some patients with FMS report clear seasonal changes in symptoms, with worsening in winter (Moldofsky, 1994), a factor to be taken into account when scheduling and evaluating the response to treatment. Since the sleep disturbance is considered to be central to most of the other symptoms of FMS, treatment should be aimed at promoting restful sleep taking into account the chronobiological features involved. Whether the pineal is involved or not in these chronobiological differences is yet unknown, but would deserve further attention (Moldofsky, 1994). On the other hand, a generalized neurovegetative disorder has been suggested to be present in FMS, which could also be the cause of reduced melatonin synthesis due to reduced badrenergic stimulation. Furthermore, the extent to which the central or the peripheral nervous systems or both play a role in the initiation of perpetuation of FMS is at present unclear. From, a neuroendocrine point of view, a series of characteristic features have been described in FMS such as hyperprolactinaemia, increased endorphins and enkephalins, low-to-normal TSH and T4 with reduced T3 (as observed in the ‘sick euthyroid syndrome’), and normal to high circulating cortisol with incomplete suppression after dexamethasone Commentary