Yellon S M
Department of Physiology, Anatomy and Pediatrics, Loma Linda University School of Medicine, CA 92350, USA.
J Biol Rhythms. 1996 Mar;11(1):4-13. doi: 10.1177/074873049601100101.
The present study tested the hypothesis that daily melatonin treatments influence the biological clock mechanism controlling the circadian melatonin rhythm. Adult male and female Djungarian hamsters in light:dark = 16L:8D (lights on 0300-1900 h) were administered melatonin subcutaneously (s.c.) each day (5 micrograms/0.2 ml saline) in the morning at 1000 h (AM) or late afternoon at 1700 h (PM); controls received a vehicle injection (CON). After 14 days, pineal and serum melatonin concentrations were determined at various times on the last day of treatment and the next day in constant darkness (no treatment). The rhythm in pineal gland melatonin content was similar in each of the three groups on the last day of treatment (about 6 h duration). On the next day in constant dark, the rising phase was advanced and duration extended by 2 h or more in melatonin-treated hamsters compared to that in CONs (ANOVA). In circulation, the melatonin rhythm in AM and PM groups was phase advanced (onset and peak) on both days of the study. Thus duration was extended by up to 4.5 h compared to that in saline-treated controls. Moreover, amplitude of the nighttime serum melatonin rise was elevated up to fivefold relative to that in the CON group (ANOVA and Accumulated Sums analysis). The effects of repeated melatonin treatments on amplitude and phase of the serum melatonin rhythm raise the possibility that the circadian clock that controls pineal gland production of melatonin may also regulate melatonin secretion. From this and another study, the apparent half-life of melatonin in circulation was estimated to be 7.5 min; the melatonin injection initially produced pharmacological concentrations that were followed by low serum melatonin levels within 2 h. Thus, in both melatonin treatment groups, the data suggest that two distinct periods of elevated serum melatonin were present each day. The cellular mechanism for melatonin action must take into consideration how a brief interruption in elevated melatonin in circulation (about 1 h in the PM group) is recognized as a continuous duration (short daylength), whereas a more extended baseline period is transduced as an abbreviated or long daylength (about 7 h in the AM group). These data further suggest that the biological clock mechanism that generates the circadian melatonin rhythm is responsive to the influence of daily melatonin treatments and presumably to the feedback action of endogenous melatonin on its own rhythm in the Djungarian hamster in long days.
每日褪黑素治疗会影响控制昼夜节律性褪黑素节律的生物钟机制。将成年雄性和雌性黑线毛足鼠置于光照：黑暗 = 16小时光照：8小时黑暗（03:00 - 19:00开灯）的环境中，每天上午10:00（AM）或下午17:00（PM）皮下注射（s.c.）褪黑素（5微克/0.2毫升生理盐水）；对照组接受溶剂注射（CON）。14天后，在治疗最后一天的不同时间以及次日持续黑暗（不治疗）状态下测定松果体和血清中的褪黑素浓度。在治疗最后一天，三组动物的松果体褪黑素含量节律相似（持续时间约6小时）。在次日持续黑暗状态下，与对照组相比，褪黑素治疗组的上升期提前，持续时间延长2小时或更长（方差分析）。在循环中，上午组和下午组的褪黑素节律在研究的两天中均出现相位提前（起始和峰值）。因此，与生理盐水处理的对照组相比，持续时间延长了多达4.5小时。此外，夜间血清褪黑素升高的幅度相对于对照组升高了五倍（方差分析和累积和分析）。重复褪黑素治疗对血清褪黑素节律的幅度和相位的影响增加了这样一种可能性，即控制松果体褪黑素产生的生物钟也可能调节褪黑素的分泌。根据本研究及另一项研究，估计循环中褪黑素的表观半衰期为7.5分钟；褪黑素注射最初产生的药理浓度在2小时内随后降至低血清褪黑素水平。因此，在两个褪黑素治疗组中，数据表明每天存在两个不同的血清褪黑素升高期。褪黑素作用的细胞机制必须考虑如何将循环中褪黑素升高的短暂中断（下午组约1小时）识别为持续时间（短日照长度），而更长的基线期则被转换为缩短的或长的日照长度（上午组约7小时）。这些数据进一步表明，产生昼夜节律性褪黑素节律的生物钟机制对每日褪黑素治疗的影响有反应，并且可能对内源性褪黑素在长日照下对其自身节律的反馈作用有反应。
