Circadian rhythm in rat brain opiate receptor

doi:10.1016/0304-3940(81)90055-0

Neuroscience Letters

Volume 21, Issue 1, 1 January 1981, Pages 45-50

https://doi.org/10.1016/0304-3940(81)90055-0 Get rights and content

Abstract

To investigate diurnal variations in opiate receptor binding, the amount of specifically bound [³H]naloxone was measured at 4-h intervals across a 24-h period in the forebrains of rats that had been housed under a controlled light-dark cycle (lights on from 07.00 to 19.00 h) for 3 weeks. A significant rhythm with a peak at 22.00 h was found, the amplitude was 46–78%. In the absence of time cues, this circadian rhythm persisted with a peak at 02.00–06.00 h and an amplitude of 88%. Scatchard analysis indicated that the differences in binding throughout the day were due not to changes in affinity, but to changes in the number of binding sites.

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Citation Excerpt :
In the present study, we exploited the natural circadian control of food intake to assess peptide dynamics in different feeding states, thereby approximating experimental conditions used in previous studies of feeding-related opioid peptide gene expression changes in the NAc (18). Rats forage for food at the beginning of the dark cycle (47). Hence, the animals were subjected to food deprivation at the beginning of the dark cycle—their natural time to eat.
Endogenous neuropeptides are important signaling molecules that function as regulators of food intake and body weight. Previous work has shown that neuropeptide gene expression levels in a forebrain reward site, the nucleus accumbens (NAc), were changed by feeding. To directly monitor feeding-induced changes in neuropeptide expression levels within the NAc, we employed a combination of cryostat dissection, heat stabilization, neuropeptide extraction and label-free quantitative neuropeptidomics via a liquid chromatography-high resolution mass spectrometry platform. Using this methodology, we described the first neuropeptidome in NAc and discovered that feeding caused the expression level changes of multiple neuropeptides derived from different precursors, especially proSAAS-derived peptides such as Big LEN, PEN and little SAAS. We further investigated the regulatory functions of these neuropeptides derived from the ProSAAS family by performing an intra-NAc microinjection experiment using the identified ProSAAS neuropeptides, 'Big-LEN′ and 'PEN′. Big LEN significantly increased rats' food and water intake, whereas both big LEN and PEN affected other behaviors including locomotion, drinking and grooming. In addition, we quantified the feeding-induced changes of peptides from hippocampus, hypothalamus and striatum to reveal the neuropeptide interplay among different anatomical regions. In summary, our study demonstrated neuropeptidomic changes in response to food intake in the rat NAc and other key brain regions. Importantly, the microinfusion of ProSAAS peptides into NAc revealed that they are behaviorally active in this brain site, suggesting the potential use of these peptides as therapeutics for eating disorders.
Biological rhythms for anaesthesia and intensive care
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La connaissance des rythmes biologiques a permis de mieux comprendre en quoi des drogues utilisées en anesthésie réanimation pouvaient avoir des effets différents selon le moment de leur administration dans le nycthèmère. Ces effets chronopharmacologiques sont à l’heure actuelle expliqués par les rythmes biologiques modifiant à la fois les paramètres pharmacocinétiques et les paramètres pharmacodynamiques de ces substances. Il en est ainsi des anesthésiques généraux et locaux, des analgésiques et des antibiotiques. Mais des données récentes mettent en évidence également que les anesthésiques généraux, probablement de part leurs effets cérébraux, modifient également la régulation des rythmes biologiques, qu’il s’agisse du rythme veille-sommeil ou du rythme de la température endogène. Cette désynchronisation des rythmes biologiques peut s’accompagner de modification de la sécrétion circadienne de nombreuses substances, notamment hormonales. Enfin, des rythmes biologiques ont été décrits en ce qui concerne la douleur, et tout récemment, le fonctionnement du système cardiovasculaire. La notion de rythme biologique doit être présente à l’esprit non seulement lors de la prise en charge clinique des patients mais également lors de la réalisation des études dans le domaine de l’anesthésie, la douleur et la réanimation.
Knowledge of biological rhythms has led to better understanding of the time-of-day dependent effects of anaesthetic drugs. These chronopharmacological effects are currently explained by the biological rhythms modulating the pharmacokinetic, toxic and pharmacodynamic parameters of these substances. Such effect has been described for general anesthetics, local anaesthetics, analgesics as well as for antibiotics. But recent data also highlight that general anaesthetics, probably part of their brain effects, also alter the regulation of biological rhythms, including the sleep-wake or the endogenous circadian temperature rhythms. This desynchronization of biological rhythms can led to disturbance of the circadian secretion of many substances, including hormones. Finally, biological rhythms have been also described with regard to physiology of pain and cardiovascular physiopathology. The concept of biological rhythm should be present in mind not only for the clinical management of patients but also for setting studies in the field of anaesthesia, pain and intensive care.
Biological rhythms and medications: A source of variability often neglected in pharmacology
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Several factors are known to induce changes in pharmacological response to drugs. The existence of biological rhythms is often neglected when assessing drug effects. Nevertheless, the best knowledge of biological rhythms have lead to medical applications, particularly chronopharmacology. Drug tolerance as well as drug effects are changing according to the hour of administration. These chronopharmacological phenomena may be explained by temporal changes in receptors drug binding or transductional effects, as well as pharmacokinetic variations in absorption, distribution, metabolism and elimination according to the moment of administration. Medical applications of such findings lead to choose the best moment of administration of the drug in order to improve the benefit/risk ratio.
Rat brain opioid peptides-circadian rhythm is under control of melatonin
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Several experiments have revealed an Endogenous Opioid System (EOS)-circadian rhythm. The brain-borne hormone, melatonin (MEL) has been shown to regulate the organism photoperiodic activity and may be implicated in the EOS-circadian rhythm. To explore this hypothesis, we studied the effect of functional pinealectomy on the EOS-circadian rhythm by measuring the immunoreactive content of Met-Enkephalin, Leu-Enkephalin and Synenkephalin in both hypothalamus and hippocampus of the rat brain, using standard radioimmunoassay procedures. Experimental animals exposed to white fluorescent light (WFL) for 15 days (<50 lux), displayed a disruption of the EOS-circadian rhythm, showing that absence of MEL induced a significant decrease of tissue content of enkephalin peptides at 01:00 h during the dark-phase of the 24-h circadian rhythm, when compared to control rats. Functional pinealectomized rats exposed to 4 or 6 h period of darkness (used to revert the effects induced by the absence of melatonin) significantly increased the tissue content of ME-IR and LE-IR, when compared to both controls and non-exposed WFL-treated rats. In addition, subcutaneous administration of exogenous melatonin (10, 100, 150, 300, 600 μg/kg), in WFL-treated animals produced significant dose-dependent increases of ME-IR in both brain regions tested. Finally, luzindole (melatonin receptor antagonist) administration, was not able to prevent the enkephalin tissue increase, induced with the MEL administration (150 μg/kg). This data suggest that MEL not only regulates the EOS-circadian rhythm, but also appears to modulate their synthesis in the rat brain from their respective neurons.
Glucocorticoid is involved in food-entrainable rhythm of μ-opioid receptor expression in mouse brainstem and analgesic effect of morphine
2006, Journal of Pharmacological Sciences
The repeated manipulation of feeding schedule has a marked influence on the chronopharmaological aspects of many drugs. In this study, we investigated the role of endogenous glucocorticoid in the mechanism by which restricting the feeding time modulates the analgesic effect of morphine. Male ICR mice were housed under a light-dark cycle (light on from 07:00 to 19:00) with food and water ad libitum or under repeated time-restricted feeding (feeding time from 09:00 to 17:00) for 2 weeks before the experiment. Under the ad libitum feeding, mRNA levels of µ-opioid receptor and its binding capacity in mouse brainstem increased around the early dark phase, following the 24-h variation in circulating glucocorticoid levels. As a consequence, potent analgesic effects of morphine were observed in mice injected with the drug during the dark phase. Daily restricted feeding modulated the time-dependency of µ-opioid receptor function, accompanied by the alteration of the rhythm in circulating glucocorticoid levels. Under the time-restricted feeding, potent analgesic effects of morphine were found in mice injected with the drug during the light phase. Because the manipulation of feeding schedule was unable to produce the food-entrainable rhythm in the expression of µ-opioid receptor in the brainstem of adrenalectomized mice, endogenous rhythm of glucocorticoid secretion seems to be involved in the mechanism by which the time-restricted feeding modulates the analgesic effects of morphine.
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Brain opioid peptides modulate feeding behavior and opiate drugs have powerful orexigenic effects in mammals. Recent studies have shown that opiate-induced eating depends, though not exclusively, on mu-opioid receptors located in the ventral striatum. Here we report that morphine orexigenic effects vary with the time of day according to a biphasic pattern. The effects first increase and then decrease during the light phase, with the peak effect occurring in the middle of this phase. This diurnal profile is shifted toward the dark phase after dopamine deafferentation of the ventral striatum. Consequently, the peak effect of morphine is delayed and occurs just before the dark phase. This finding suggests that mesolimbic dopamine transmission contributes to the neural mechanisms that normally drive the circadian timing of opioid-dependent feeding.

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Circadian rhythm in rat brain opiate receptor

Abstract

Biochem. Pharmacol.

Biochem. Pharmacol.

Europ. J. Pharmacol.

Brain Res.

Brain Res.

Europ. J. Pharmacol.

Seasonal and circadian monoamine variations in human brains examined post mortem

Acta psychiat. scand.

Naloxone decreases diurnal variation in pain sensitivity and somatosensory evoked potentials

Life Sci.

Hyperalgesia induced by naloxone follows diurnal rhythm in responsivity to painful stimuli

Science

The acute toxicity of drugs acting at cholinoceptive sites and 24-hour rhythm in brain acetylcholine

Arch. Toxicol.

Acetylcholine concentrations in rat brain

Science