An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans

1. Non-image forming, irradiance-dependent responses mediated by the human eye include synchronisation of the circadian axis and suppression of pineal melatonin production. The retinal photopigment(s) transducing these light responses in humans have not been characterised. 2. Using the ability of light to suppress nocturnal melatonin production, we aimed to investigate its spectral sensitivity and produce an action spectrum. Melatonin suppression was quantified in 22 volunteers in 215 light exposure trials using monochromatic light (30 min pulse administered at circadian time (CT) 16–18) of different wavelengths (gmax 424, 456, 472, 496, 520 and 548 nm) and irradiances (0.7–65.0 μW cm_2). 3. At each wavelength, suppression of plasma melatonin increased with increasing irradiance. Irradiance–response curves (IRCs) were fitted and the generated half-maximal responses (IR50) were corrected for lens filtering and used to construct an action spectrum. 4. The resulting action spectrum showed unique short-wavelength sensitivity very different from the classical scotopic and photopic visual systems. The lack of fit (r2 < 0.1) of our action spectrum with the published rod and cone absorption spectra precluded these photoreceptors from having a major role. Cryptochromes 1 and 2 also had a poor fit to the data. Fitting a series of Dartnall nomograms generated for rhodopsin-based photopigments over the gmax range 420–480 nm showed that rhodopsin templates between gmax 457 and 462 nm fitted the data well (r2 ≥ 0.73). Of these, the best fit was to the rhodopsin template with gmax 459 nm (r2 = 0.74). 5. Our data strongly support a primary role for a novel short-wavelength photopigment in lightinduced melatonin suppression and provide the first direct evidence of a non-rod, non-cone photoreceptive system in humans

An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans

1. Non-image forming, irradiance-dependent responses mediated by the human eye include synchronisation of the circadian axis and suppression of pineal melatonin production. The retinal photopigment(s) transducing these light responses in humans have not been characterised. 2. Using the ability of light to suppress nocturnal melatonin production, we aimed to investigate its spectral sensitivity and produce an action spectrum. Melatonin suppression was quantified in 22 volunteers in 215 light exposure trials using monochromatic light (30 min pulse administered at circadian time (CT) 16–18) of different wavelengths (gmax 424, 456, 472, 496, 520 and 548 nm) and irradiances (0.7–65.0 μW cm_2). 3. At each wavelength, suppression of plasma melatonin increased with increasing irradiance. Irradiance–response curves (IRCs) were fitted and the generated half-maximal responses (IR50) were corrected for lens filtering and used to construct an action spectrum. 4. The resulting action spectrum showed unique short-wavelength sensitivity very different from the classical scotopic and photopic visual systems. The lack of fit (r2 < 0.1) of our action spectrum with the published rod and cone absorption spectra precluded these photoreceptors from having a major role. Cryptochromes 1 and 2 also had a poor fit to the data. Fitting a series of Dartnall nomograms generated for rhodopsin-based photopigments over the gmax range 420–480 nm showed that rhodopsin templates between gmax 457 and 462 nm fitted the data well (r2 ≥ 0.73). Of these, the best fit was to the rhodopsin template with gmax 459 nm (r2 = 0.74). 5. Our data strongly support a primary role for a novel short-wavelength photopigment in lightinduced melatonin suppression and provide the first direct evidence of a non-rod, non-cone photoreceptive system in humans

Melatonin administration can entrain the free-running circadian system of blind subjects

Although melatonin treatment has been shown to phase shift human circadian rhythms, it still remains ambiguous as to whether exogenous melatonin can entrain a free-running circadian system. We have studied seven blind male subjects with no light perception who exhibited free-running urinary 6-sulphatoxymelatonin (aMT6s) and cortisol rhythms. In a single-blind design, five subjects received placebo or 5 mg melatonin p.o, daily at 2100 h for a full circadian cycle (35-71 days). The remaining two subjects also received melatonin (35-62 days) but not placebo. Urinary aMT6s and cortisol (n=7) and core body temperature (n=l) were used as phase markers to assess the effects of melatonin on the circadian system. During melatonin treatment, four of the seven free-running subjects exhibited a shortening of their cortisol circadian period (tau). Three of these had taus which were statistically indistinguishable from entrainment. In contrast, the remaining three subjects continued to free-run during the melatonin treatment at a similar tau as prior to and following treatment. The efficacy of melatonin to entrain the free-running cortisol rhythms appeared to be dependent on the circadian phase at which the melatonin treatment commenced. These results show for the first time that daily melatonin administration can entrain free- running circadian rhythms in some blind subjects assessed using reliable physiological markers of the circadian system

Extraocular light exposure does not suppress plasma melatonin in humans.

Light affects the circadian axis in at least two ways. It can cause the acute suppression of pineal melatonin synthesis, and/or a phase-shift of the circadian oscillator. As recent evidence has suggested that extraocular light exposure may cause phase-shifts of the circadian clock, we have investigated whether suppression of melatonin can be induced by the same type of light exposure. In the first study subjects’ eyes were exposed to white light (2250 lux for 30 min) via a fibre optic cable. As expected, suppression of nighttime plasma melatonin levels (61 ± 6%) was observed. In the second study, light of the same quality but higher intensity (14,000 or 67,500 lux for 180 mins) was delivered in the same manner to the popliteal region behind the subjects’ knees, whilst shielding their eyes. No suppression of plasma melatonin levels (4 ± 7%) was detected in any of the subjects. Thus, extraocular photoreception, if it exists in mammals, does not affect the suprachiasmatic nuclei-pineal pathway

Extraocular light exposure does not suppress plasma melatonin in humans

Light affects the circadian axis in at least two ways. It can cause the acute suppression of pineal melatonin synthesis, and/or a phase-shift of the circadian oscillator. As recent evidence has suggested that extraocular light exposure may cause phase-shifts of the circadian clock, we have investigated whether suppression of melatonin can be induced by the same type of light exposure. In the first study subjects’ eyes were exposed to white light (2250 lux for 30 min) via a fibre optic cable. As expected, suppression of nighttime plasma melatonin levels (61 ± 6%) was observed. In the second study, light of the same quality but higher intensity (14,000 or 67,500 lux for 180 mins) was delivered in the same manner to the popliteal region behind the subjects’ knees, whilst shielding their eyes. No suppression of plasma melatonin levels (4 ± 7%) was detected in any of the subjects. Thus, extraocular photoreception, if it exists in mammals, does not affect the suprachiasmatic nuclei-pineal pathway

Extraocular light exposure does not suppress plasma melatonin in humans.

Light affects the circadian axis in at least two ways. It can cause the acute suppression of pineal melatonin synthesis, and/or a phase-shift of the circadian oscillator. As recent evidence has suggested that extraocular light exposure may cause phase-shifts of the circadian clock, we have investigated whether suppression of melatonin can be induced by the same type of light exposure. In the first study subjects’ eyes were exposed to white light (2250 lux for 30 min) via a fibre optic cable. As expected, suppression of nighttime plasma melatonin levels (61 ± 6%) was observed. In the second study, light of the same quality but higher intensity (14,000 or 67,500 lux for 180 mins) was delivered in the same manner to the popliteal region behind the subjects’ knees, whilst shielding their eyes. No suppression of plasma melatonin levels (4 ± 7%) was detected in any of the subjects. Thus, extraocular photoreception, if it exists in mammals, does not affect the suprachiasmatic nuclei-pineal pathway