Reciprocal Relationships between General (Propofol) Anesthesia and Circadian Time in Rats

Challet, Étienne; Gourmelen, Sylviane; Pévet, Paul; Oberling, Philippe; Pain, Laure

doi:10.1038/sj.npp.1301081

Cited by 51 publications

(40 citation statements)

References 37 publications

(45 reference statements)

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“…In contrast to Cheeseman et al (9) and Challet et al (10), isoflurane administration caused suppression of circadian gene expression but did not cause a shift in circadian pattern in investigated tissues. Cheeseman et al (9) kept animals in a DD cycle after anaesthesia administration, and they found a phase shift in circadian gene expression.…”

Section: Discussioncontrasting

confidence: 49%

“…They concluded that general anaesthesia during the day caused a persistent and marked shift of the clock, effectively inducing 'jet lag' and causing impaired time perception. Challet et al (10) reported that 30 min propofol administration causes a one-hour time shift in circadian rhythms (activity and temperature) in rats which were kept in a darkdark (DD) cycle during the study period.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Day-Time Isoflurane Administration Suppresses Circadian Gene Expressions in Both the Brain and a Peripheral Organ, Liver

Gökmen¹,

Barış²,

Öçmen³

et al. 2017

Turk J Anaesth Reanim

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Section: Discussioncontrasting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Day-Time Isoflurane Administration Suppresses Circadian Gene Expressions in Both the Brain and a Peripheral Organ, Liver

Gökmen¹,

Barış²,

Öçmen³

et al. 2017

Turk J Anaesth Reanim

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“…Consistent with this finding, rats receiving an i.p. injection of propofol at night-time sleep for a shorter duration compared with animals tested with propofol during the daytime, which could possibly be due to faster propofol metabolism (Challet et al, 2007). Thus, variation in brain CYP2B levels may introduce noise or error into rat studies, if the drugs tested are CYP2B substrates and the experiments vary in the time of day.…”

Section: Discussionmentioning

confidence: 97%

Drug Metabolism within the Brain Changes Drug Response: Selective Manipulation of Brain CYP2B Alters Propofol Effects

Khokhar

Tyndale

2010

Neuropsychopharmacol

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Drug-metabolizing cytochrome P450 (CYPs) enzymes are expressed in the liver, as well as in extrahepatic tissues such as the brain. Here we show for the first time that drug metabolism by a CYP within the brain, illustrated using CYP2B and the anesthetic propofol (2, 6-diisopropylphenol, Diprivan), can meaningfully alter the pharmacological response to a CNS acting drug. CYP2B is expressed in the brains of animals and humans, and this CYP isoform is able to metabolize centrally acting substrates such as propofol, ecstasy, and serotonin. Rats were given intracerebroventricularly (i.c.v.) injections of vehicle, C8-xanthate, or 8-methoxypsoralen (CYP2B mechanism-based inhibitors) and then tested for sleep time following propofol (80 mg/kg intraperitoneally). Both inhibitors significantly increased sleep-time (1.8- to 2-fold) and brain propofol levels, while having no effect on plasma propofol levels. Seven days of nicotine treatment can induce the expression of brain, but not hepatic, CYP2B, and this induction reduced propofol sleep times by 2.5-fold. This reduction was reversed in a dose-dependent manner by i.c.v. injections of inhibitor. Sleep times correlated with brain (r=0.76, P=0.0009), but not plasma (r=0.24, P=0.39) propofol concentrations. Inhibitor treatments increased brain, but not plasma, propofol levels, and had no effect on hepatic enzyme activity. These data indicate that brain CYP2B can metabolize neuroactive substrates (eg, propofol) and can alter their pharmacological response. This has wider implications for localized CYP-mediated metabolism of drugs, neurotransmitters, and neurotoxins within the brain by this highly variable enzyme family and other CYP subfamilies expressed in the brain.

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“…Furthermore, some anesthetics can affect behavioral and physiological rhythms in rodents. Whereas the benzodiazepine midazolam and the opiate fentanyl can cause phase advances and delays in locomotor activity depending on the time of administration (25), the anesthetic propofol induces only phase advances (26). Moreover, the inhalational anesthetic sevoflurane has been shown to cause phase delays in activity of ∼1 h when administered during the subjective day (27).…”

Section: Discussionmentioning

confidence: 99%

General anesthesia alters time perception by phase shifting the circadian clock

Cheeseman

Winnebeck

Millar

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Following general anesthesia, people are often confused about the time of day and experience sleep disruption and fatigue. It has been hypothesized that these symptoms may be caused by general anesthesia affecting the circadian clock. The circadian clock is fundamental to our well-being because it regulates almost all aspects of our daily biochemistry, physiology, and behavior. Here, we investigated the effects of the most common general anesthetic, isoflurane, on time perception and the circadian clock using the honeybee (Apis mellifera) as a model. A 6-h daytime anesthetic systematically altered the time-compensated sun compass orientation of the bees, with a mean anticlockwise shift in vanishing bearing of 87°in the Southern Hemisphere and a clockwise shift in flight direction of 58°in the Northern Hemisphere. Using the same 6-h anesthetic treatment, time-trained bees showed a delay in the start of foraging of 3.3 h, and whole-hive locomotor-activity rhythms were delayed by an average of 4.3 h. We show that these effects are all attributable to a phase delay in the core molecular clockwork. mRNA oscillations of the central clock genes cryptochrome-m and period were delayed by 4.9 and 4.3 h, respectively. However, this effect is dependent on the time of day of administration, as is common for clock effects, and nighttime anesthesia did not shift the clock. Taken together, our results suggest that general anesthesia during the day causes a persistent and marked shift of the clock effectively inducing "jet lag" and causing impaired time perception. Managing this effect in humans is likely to help expedite postoperative recovery.chronobiology | anesthesiology | post-operative sleep disruption E ver since "Ether Day" in 1846, when William Morton administered the first general anesthetic, anesthesia has been used to alleviate pain and enable a wide range of surgical procedures that were not previously possible. Today, an estimated 234 million operations requiring anesthesia occur around the world each year (1). Despite the ubiquity and importance of general anesthesia, the mechanisms by which anesthetics work to "put you to sleep" remain unclear. Recent evidence suggests that most general anesthetics act, at least in part, on the same brain centers as those involved in the control of sleep (2) and that they may "hijack" endogenous GABA-ergic (γ-aminobutyric acid) sleep-controlling pathways to exert their effects on consciousness (3). The effect of anesthesia on brain activity parallels some of the features of sleep (3). However, there are obvious differences. For example, a common patient response on emerging from anesthesia is disorientation and the feeling that time has not passed. This is in stark contrast to sleep, where one often wakes up just before the alarm sounds aware that time has passed during the night.Daily sleep timing relies on the endogenous circadian clock, which drives daily rhythms in biochemistry, physiology, and behavior. In animals, this clock is controlled by a set of conserved and well-char...

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Reciprocal Relationships between General (Propofol) Anesthesia and Circadian Time in Rats

Cited by 51 publications

References 37 publications

Day-Time Isoflurane Administration Suppresses Circadian Gene Expressions in Both the Brain and a Peripheral Organ, Liver

Day-Time Isoflurane Administration Suppresses Circadian Gene Expressions in Both the Brain and a Peripheral Organ, Liver

Drug Metabolism within the Brain Changes Drug Response: Selective Manipulation of Brain CYP2B Alters Propofol Effects

General anesthesia alters time perception by phase shifting the circadian clock

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