MINI REVIEW

Melatonin and anesthesia: a clinical perspective

It is believed that Galen (c. 130–210 AD), a Greekphysician and philosopher, was the first to provideanatomical and functional descriptions of the pineal gland

[1]. In the first half of the 17th century, the Frenchphilosopher Rene Descartes thought that the pineal glandwas involved in sensation, imagination, memory, and bodymovements, and he viewed it as the �the center of the spiritor the seat of the soul� in his writings [1]. The pineal glandwas first identified as the source of melatonin in 1958 byAaron Lerner, and colleagues [2]. Lerner and co-workers

isolated an active factor (N-acetyl-5-methoxytryptamine)from beef pineal extracts and called this substance melato-nin because of its ability to aggregate pigment granules in

amphibian melanophores [2].

Melatonin synthesis and metabolism

Melatonin is a nocturnal hormone that is produced by thepineal gland and by other tissues [3]. In the pineal gland, its

production is stimulated by darkness, independent of sleep,and is inhibited by exposure to light. Melatonin biosynthe-sis is under sympathetic control and is triggered by an

increase in pinealocyte cyclic adenosine monophosphate(cAMP) levels secondary to b1-adrenergic receptor activa-tion by norepinephrine [4]. The increases in cAMP activatearylalkamine N-acetyltransferase, the enzyme responsible

for the conversion of serotonin into N-acetylserotonin.Some, but not all, of the clock genes that are expressed inthe pineal gland, such as Per1, are also regulated by

norepinephrine [5].Synthesis of melatonin begins with the amino acid

L-tryptophan and proceeds in a relatively straightforward

manner to yield the final product [6, 7]. Fundamental toour appreciation of the role of melatonin in regulatingcircadian rhythms was the demonstration that O-methy-lation of N-acetylserotonin is light dependent [8], and that

the light-dependent effects are mediated by sympatheticinput arising in the superior cervical ganglia [9]. Serotonin

Abstract: The hypnotic, antinociceptive, and anticonvulsant properties of

melatonin endow this neurohormone with the profile of a novel hypnotic-

anesthetic agent. Sublingually or orally administered melatonin is an effective

premedicant in adults and children. Melatonin premedication like

midazolam is associated with sedation and preoperative anxiolysis, however,

unlike midazolam these effects are not associated with impaired psychomotor

skills or the quality of recovery. Melatonin administration also is associated

with a tendency toward faster recovery and a lower incidence of

postoperative excitement than midazolam. Oral premedication with

0.2 mg/kg melatonin significantly reduces the propofol and thiopental doses

required for loss of responses to verbal commands and eyelash stimulation.

In rats, melatonin and the more potent melatonin analogs 2-bromomelatonin

and phenylmelatonin have been found to have anesthetic properties similar

to those of thiopental and propofol, with the added advantage of providing

potent antinociceptive effects. The exact mechanism(s) by which structurally

diverse intravenous and volatile anesthetics produce general anesthesia is still

largely unknown, but positive modulation of c-aminobutyric acid type A

(GABAA) receptor function has been recognized as an important and

common pathway underlying the depressant effects of many of these agents.

Accumulating evidence indicates that there is interplay between the

melatonergic and GABAergic systems, and it has been demonstrated that

melatonin administration produces significant, dose-dependent increases in

GABA concentrations in the central nervous system. Additional in vitro data

suggest that melatonin alters GABAergic transmission by modulating

GABAA receptor function. Of greater importance, data from in vivo studies

suggest that the central anesthetic effects of melatonin are mediated, at least

in part, via GABAergic system activation, as they can be blocked or reversed

by GABAA receptor antagonists. Further work is needed to better

understand the general anesthetic properties of melatonin at the molecular,

cellular, and systems levels.

Mohamed Naguib1, VijayaGottumukkala1 and Peter A.Goldstein2

1Department of Anesthesiology and Pain

Medicine, The University of Texas M. D.

Anderson Cancer Center, Houston, TX, USA;2Department of Anesthesiology, Weill Medical

College of Cornell University, New York, NY,

USA

Key words: analgesia, anesthesia, melatonin

Address reprint requests to Mohamed Naguib,

Department of Anesthesiology and Pain

Medicine, Unit 409, The University of Texas

M.D. Anderson Cancer Center, 1400 Holco-

mbe Boulevard, Houston, TX 77030, USA.

E-mail: Naguib@mdanderson.org

Received September 17, 2006;

accepted September 18, 2006.

J. Pineal Res. 2007; 42:12–21Doi: 10.1111/j.1600-079X.2006.00384.x

� 2006 The AuthorsJournal compilation � 2006 Blackwell Munksgaard

Journal of Pineal Research

12

and melatonin synthesis show marked diurnal rhythms,such that pineal serotonin levels are markedly higherduring the day than at night [10], while the levels of its

downstream derivatives, N-acetylserotonin and melatonin,peak during the night [11]. The conversion of serotonin toN-acetylserotonin has long been thought to be the rate-limiting step in melatonin synthesis, and driving the

underlying diurnal rhythm in melatonin levels is acorresponding norepinephrine-dependent change in theactivity level of arylalkamine N-acetyltransferase [12, 13].

Paralleling the increase in enzymatic activity is a corres-ponding increase in the transcription of N-acetyltransf-erase mRNA [14, 15]; recent work suggests, however, that

N-acetyltransferase activity is not the rate-limiting step inmelatonin synthesis [16, 17]. Melatonin is not stored insidethe pineal gland, and once synthesized, it diffuses into thebloodstream and eventually is distributed to all tissues

because of its lipophilicity.Circulating melatonin is metabolized extensively by the

liver mixed-function oxidase system (the CYP system or the

cytochrome P-450 system) to 6-hydroxymelatonin, thenconjugated (via sulpho- and to a lesser extent glucurono-conjugation); conjugated melatonin and small quantities of

unmetabolized melatonin are excreted in the urine [18]. Inaddition to hepatic metabolism, oxidative pyrrole-ringcleavage appears to be the major metabolic pathway in

tissues, including the central nervous system (CNS) [19].The primary metabolite is N1-acetyl-N2-formyl-5-meth-oxykynuramine (AFMK), which is deformylated, eitherby arylamine formamidase or hemoperoxidases, to N1-

acetyl-5-methoxykynuramine (AMK); the latter metaboliteis a potent antioxidant and supports mitochondrial func-tion [20].

Physiological roles of melatonin

Melatonin has several important physiological functions,including regulation of circadian rhythms [21], regulation ofthe reproductive axis [22], and antioxidant, oncostatic, anti-inflammatory, and anticonvulsant effects [23–25]. The

ability of melatonin to maintain mitochondrial functionof body organs in the face of oxidative stress is wellestablished [26, 27]. It has also been demonstrated that

melatonin dramatically improves survival rates in humannewborns with septic shock [28]. Interestingly, exogenouslyadministered melatonin protects against anesthetic-induced

apoptotic neurodegeneration in the developing rat brain,particularly in the cerebral cortex and anterior thalamus[29, 30], suggesting that melatonin serves a neuroprotective

function in these regions [31]. This protective effect is likelymediated via inhibition of the mitochondrial apoptoticcascade. Melatonin administration is associated withupregulation of the anti-apoptotic protein bcl-XL, reduc-

tion in anesthesia-induced cytochrome c release into thecytoplasm, and decrease in anesthesia-induced activationof caspase-3 [29]. These potentially beneficial effects

have not yet been explored, however, in either surgicalpatients or patients in critical care settings, and in arecent review, melatonin was not considered among the

antioxidant therapies that could be used for myocardialprotection [32].

Melatonin is perhaps best known by medical profession-als and laypersons alike for its hypnotic actions. Thehypnotic effects of melatonin are considered an integral

component of its physiological role and will be addressed indetail later in this review; the other physiologic roles ofmelatonin are beyond the scope of this review and arediscussed elsewhere (see [24, 25]).

Effect of anesthesia and surgery onmelatonin homeostasis

Anesthesia and surgery reportedly alter the normal circa-dian pattern of melatonin production [33–35], but the

evidence in the literature on the magnitude of disruption ofmelatonin homeostasis is not consistent. Reber et al. [33]reported that isoflurane and propofol anesthesia elicitedelevated plasma melatonin levels. In the recovery period,

this elevation persisted in patients anesthetized with isoflu-rane, but gradually decreased in patients anesthetized withpropofol. In contrast, Karkela et al. [35] reported that both

spinal and general anesthesia significantly decreased mela-tonin secretion during the first postoperative eveningwhen compared with the preoperative evening; they also

noticed a postanesthesia phase delay in melatonin secretion.Nishimura et al. [34] were not able, however, to demon-strate any significant changes in melatonin secretion in

patients who underwent major surgery.The conflicting results on melatonin secretion in the

perioperative period in these studies could be due to thedifferences in the methodology of melatonin concentra-

tion measurement, differences in the duration and/orcomplexity of surgical procedures, differences in preme-dicant administration, differences in anesthetic techniques,

and other pharmacological interventions (use of anxioly-tics, opioids, anticholinergics, anticholinesterases, andbeta-blockers) during the perioperative period. Further

studies are needed to better understand the short- andlong-term effects of surgery on melatonin circadianrhythm.

Hypnotic effects of exogenouslyadministered melatonin

The role of melatonin in regulating circadian rhythms iswell described [36–39]. Building on the experimentalliterature in animals [40] and anecdotal observations in

humans [41], Anton-Tay and co-workers [42] were thefirst to demonstrate clearly that exogenously administeredmelatonin has hypnotic properties (i.e. produces loss of

consciousness) in human subjects, and that the loss ofconsciousness is accompanied by a pattern of electroen-cephalographic (EEG) activity similar to that seen duringintravenous and volatile anesthetic-induced loss of con-

sciousness [43, 44].Subsequent work has demonstrated that exogenously

administered melatonin markedly decreases the mean

latency of sleep onset time in young [45] and elderlysubjects [46]. Orally administered melatonin (5 mg) is usedto alleviate jet lag and fatigue after long flights [47], for

treatment of sleep disorders in blind subjects [48], inpatients with delayed phase sleep syndrome [48], and as a

Melatonin and anesthesia

13

preoperative medication in both pediatric [49] and adultsurgical patients [50, 51]. In elderly patients, preoperativeanxiety at 90 min decreased by 33% in subjects premedi-

cated with 10 mg melatonin PO, when compared with a21% reduction in the placebo group, but the difference wasnot significant [52]. A major deficiency of this study,however, is that the sedative effects of melatonin were not

objectively measured, thus limiting the validity of theobservations.Naguib and co-workers [49–51] noted that premedication

with 0.05, 0.1, or 0.2 mg/kg sublingual/oral melatonin,unlike midazolam, is associated with preoperative anxioly-sis and sedation in adults and children without impairment

of psychomotor skills or impact on the quality of recovery;if anything, preoperative melatonin administration wasassociated with a tendency toward faster recovery and alower incidence of postoperative excitement than midazo-

lam. Further highlighting the differences between therapeu-tically administered melatonin and benzodiazepines orbarbiturates were the findings that benzodiazepines

decrease the duration of rapid eye movement (REM) sleepafter single administration of a high dose [53] or long-termadministration of a low dose [54], thus negatively influen-

cing sleep quality. In contrast, administration of a singlelow dose of melatonin does not suppress REM sleep [55].Furthermore, unlike benzodiazepines, melatonin does not

induce �hangover� effects [55].Recently, a meta-analysis of randomized control trials on

the effects of exogenous melatonin on sleep [56] found thatmelatonin treatment significantly reduced sleep onset

latency, increased sleep efficiency, and increased total sleepduration, thereby validating the original observations. Ashas been previously pointed out [57], and it is worth

repeating here, reported differences in the activity ofexogenously administered melatonin may reflect differencesin dose/preparation, subject profiles, and time of adminis-

tration.Oral premedication with 0.2 mg/kg melatonin signifi-

cantly reduces the propofol and thiopental doses required

for loss of responses to verbal commands and eyelashstimulation [58]. At the ED50 values reflecting loss ofresponses to verbal command and eyelash reflex, therelative potency of propofol after melatonin premedication

was 1.7–1.8 times greater than that of propofol afterplacebo [58]. Similarly, the relative potency of thiopentalwas 1.3–1.4 times greater after premedication with melato-

nin than that of thiopental after placebo [58]. In rats, orallyadministered melatonin has been shown to potentiate theanesthetic effects of thiopental and ketamine [59]. Further-

more, intraperitoneal injection of 100 mg/kg melatoninsignificantly reduces MAC for isoflurane in rats by 24%when compared with control [60].The above observations raised the question whether

melatonin might be suitable as an anesthetic inductionagent. Data from in vivo rat models have shown that bothmelatonin and the more potent melatonin analogs

2-bromomelatonin and phenylmelatonin possesses anes-thetic properties [44, 61–63]. Anesthetic doses of melatoninproduced effects on processed electroencephalographic

variables similar to those of thiopental and propofol [44].The profile of the hypnotic properties of 2-bromomelatonin

and phenylmelatonin is similar to that induced by propofolin that both compounds have a rapid onset and a shortduration of action. Unlike propofol and thiopental, mela-

tonin and melatonin analogs possess potent antinociceptiveanticonceptive effects [44, 62]. Evidence suggests thatmelatonin-induced analgesia results from the release ofb-endorphin [64]. Those data support the notion that

melatonin, or one of its analogs, might find use as ananesthetic agent.

Mechanisms of general anesthesia

To explore the possible means by which melatonin

induces general anesthesia, we need to dissect themechanisms involved. General anesthesia is a pharmaco-logically induced state that entails amnesia, analgesia,hypnosis (unconsciousness), immobility, and blunted

autonomic responsiveness. The molecular and cellularmechanisms governing general anesthesia are slowly beinguncovered, but in many cases remain poorly understood.

General anesthesia can be induced by a variety ofintravenous and inhalational agents acting at differenttarget sites [65–67]. Thus, at the anatomic level, general

anesthetic-induced immobility was thought to be spinallymediated [68], while the amnestic and hypnotic effectswere thought to result from modulation of thalamocor-

tical networks and the midbrain reticular formation [65,69, 70]. The distinction between spinal and supraspinalsites of action may not be correct, however [71–74];recent evidence indicates that immobility produced by

propofol [75] or thiopental [72] is probably mediatedprimarily by supraspinal actions, and not as previouslyargued at the level of the spinal cord.

At the molecular level, general anesthetics enhancethe function of inhibitory c-aminobutyric acid type A(GABAA) and glycine receptors and inhibit excitatory

nicotinic acetylcholine, serotonin type 3, and N-methyl-d-aspartate (NMDA) receptors. Positive modulation ofGABAA receptor function has been recognized as animportant component of the CNS depressant effects of

many intravenous anesthetics, including propofol, barbit-urates, and etomidate [76]. Other members of the ligand-gated ion channel family have been identified as molecular

targets of other anesthetics. For instance, heteromericneuronal a4b4 nicotinic acetylcholine receptors in theCNS were found to be potential targets for volatile

anesthetics and the intravenous agent ketamine [77, 78].Ketamine, known to be an inhibitor at the NMDAreceptor, has no or little effect on GABAA receptor in a

clinically relevant concentration range [78, 79]. It seems,therefore, that intravenous anesthetics with different beha-vioral profiles act on different and specific ligand-gated ionchannels to produce a specific anesthetic behavior.

Whether the anesthetic effect of melatonin is due to adirect effect on melatonin receptors is largely unknown.Melatonin receptors, per se, are not routinely considered

molecular targets for general anesthetic action. There isevidence to suggest, however, that the central effects ofmelatonin involve, at least in part, facilitation of GABAer-

gic transmission by modulating the GABA receptor[80–82].

Naguib et al.

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CNS distribution of melatonin binding sites

Melatonin receptor mRNAs and proteins

Autoradiographic studies have demonstrated marked

regional melatonin binding in the rodent brain [83–85].Notably, while [125I]iodomelatonin binding is well des-cribed in the suprachiasmatic nucleus (SCN), it is also

clearly detected in anterior thalamic nuclei [83–85]; thefunctional significance of melatonin binding sites in thethalamus is unknown. However, the anterior thalamus may

be important in the formation of episodic memory [86–88]and sleep/wake states, given its connections with thereticular thalamic nucleus [89–92], a critical structure inthe genesis of oscillatory electrical activity thought to be

vital in establishing different states of consciousness[93–95].

To date, three melatonin receptors have been cloned:

MT1 (formerly Mel-1a [96]), MT2 (formerly Mel-1b [97]),and Mel-1c [98, 99], although only MT1 and MT2 appear tobe expressed in mammals; these are the two melatonin

receptors recognized by the International Union of Phar-macology (IUPHAR; http://www.iuphar-db.org/ – data-base accessed March 25, 2006) [99–101].

Consistent with the data from binding studies, data fromin situ hybridization studies indicate that RNA for MT1,but not for MT2, is present in the mammalian hypotha-lamic SCN and the hypophyseal pars tuberalis [96, 97, 102,

103], but more recent work suggests that MT1 mRNA ismore widely distributed than previously thought [104, 105].

Our knowledge of the distribution of MT1 and MT2

proteins in the brain is incomplete. Western immunoblots,using tissue obtained from postmortem human brains, havedetected MT1 receptor protein in homogenates prepared

from prefrontal cortex, putamen, caudate nucleus, nucleusaccumbens, substantia nigra, amygdala, and hippocampus[105]. At the immunohistochemical level, MT1 immuno-labeling has been detected in hippocampal pyramidal and

dentate gyrus neurons (with the strongest labeling observedin CA1 neurons [106]) as well as in cerebellar granule andstellate basket neurons [104, 107] while MT2 immunolabe-

ling appears to be more prominent in the CA3 and CA4(dentate gyrus) regions of the hippocampus [108].

Melatonin-mediated signal transduction

MT1 and MT2 receptors are G-protein coupled receptors

with complex signal transduction pathways (Fig. 1) [101,109]. Although the metabotropic transduction pathways formelatonin are well described (Fig. 1), there is a body ofliterature suggesting that melatonin has modulatory effects

independent of those pathways. Exogenously appliedmelatonin inhibits single unit activity recorded in SCNneurons in vitro [110–112] as a function of circadian clock

time [111, 113–115], and under comparable conditions,timed melatonin application phase shifts the circadianrhythm of electrical activity in SCN neurons [112, 116]. In

mice lacking the MT1 receptor, melatonin-induced inhibi-tion of SCN neuronal firing is significantly impaired whilethe phase-shifting effect on SCN firing activity is preserved[117], indicating that melatonin has modulatory effects

independent of MT1 receptors. The in vivo phase-shiftingeffect of melatonin appears to be mediated by MT2receptors [118, 119], however, and results from (at least in

part) MT2-receptor desensitization in SCN neurons [120].It is worth noting that the strain of mice (along with 30other mouse lines) used in the study by Liu et al. [117] doesnot synthesize melatonin [121], suggesting that regulation

of circadian rhythms, at least in mice, may be in factindependent of melatonin.Exogenously applied melatonin inhibits single unit

activity recorded in SCN neurons in vitro [110–112] as afunction of circadian clock time [111, 113–115], and thisinhibition may be due to activation of a barium-sensitive

outward potassium current and inhibition of the inward-rectifying cation current (hyperpolarization-activated cat-ion current, Ih) [122, 123].

Fig. 1. Putative signaling pathways activated by MT1 and MT2melatonin receptors. (A) Multiple signaling pathways for MT1melatonin receptors coupled to Gai and Gaq. (B) Signaling path-ways coupled to MT2 melatonin receptor activation. No directevidence for MT2 receptors coupling to Gq has been reported, sothe pathway leading to PCK activation remains putative. PIP2,phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C;DAG, diacylglycerol; PKA, protein kinase A; CREB, cAMP-responsive element binding protein; ER, endoplasmic reticulum;VDCC, voltage-dependent Ca2+ channel; BKCa, Ca

2+-activatedpotassium channel; FP, receptor for prostaglandin F2a; PGF2a,prostaglandin F2a; IBMX, isobutylmethylxanthine; ATP, adeno-sine triphosphate; MLT, melatonin; GTP, guanine triphosphate;GMP, guanine monophosphate. Reprinted with permission fromMasana and Dubocovich, Sci STKE 2001, 107:PE39. Copyright2001 AAAS. http://www.sciencemag.org.

Melatonin and anesthesia

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Melatonin–GABAergic interaction

The pineal gland provides afferent fibers to the SCN, and as

already discussed, is the primary source of melatoninreleased there. The SCN, in turn, sends projection fibersthroughout the hypothalamus [124], notably to the sub-paraventricular zone (SPZ) and the dorsomedial nucleus of

the hypothalamus (DMH) [125–127]; the DMH is asignificant source of GABAergic input to the ventrolateralpreoptic nucleus (VLPO) [127, 128]. The VLPO is part of an

endogenous sleep pathway [69] which, when activated,inhibits histaminergic neurons in the tubomamillary nuc-leus (TMN) [129], thus depriving cortical and subcortical

structures of signals promoting arousal and thereby facili-tating a transition from wakefulness to sleep.Suprachiasmatic nucleus neurons provide both fast

excitatory and inhibitory drive, mediated respectively by

glutamate and GABA, to both the paraventricular nucleus[130, 131] and the VLPO [132]. Of equal importance, SCNneurons form GABAA-mediated local inhibitory circuits

within the SCN [133], and it is thought that GABA, actingthrough GABAA receptors, helps synchronize SCN clockcells [134].

As already indicated, melatonin inhibits action potentialfiring in SCN neurons; thus, one effect of melatonin releaseis to decrease excitatory and inhibitory drive arising in the

SCN to those sites receiving SCN projection fibers.Depending on the relative strengths of those inputs, thepredominant effect in the relevant region will, at least intheory, be either a loss of inhibition (leading to an increase

in excitation) or a loss of excitation (leading to an increasein inhibition). Of course, such an argument presupposes theexistence of a linear signaling pathway, whereas the reality

is far more complicated, reflecting an extensive network ofinterconnected pathways utilizing a number of differenttransmitter systems [128, 135, 136].

The validity of this caveat can be seen in the followingscenario. The SCN provides GABAergic input to the DMH[137, 138], which in turn provides inhibitory input to theVLPO [127]. Thus, in theory, melatonin-induced inhibition

of spike firing in the SCN should disinhibit spike firing inthe DMH, leading to an increase in inhibitory synaptictransmission in the VLPO (thus decreasing inhibitory

output) and consequently, an increase in histaminergic(excitatory) cortical and subcortical activation, and anincrease in arousal. This is not the case, however, suggest-

ing that feedback inhibition within the SCN or additionalregulatory pathways, or both, provides significant modula-tion of the circuit described above.

Alternatively, it is possible that melatonin modulatesionotropic receptor function, particularly that of GABAA

receptors [139, 140]. A wide variety of general anesthetics,including intravenous and volatile agents, act as positive

allosteric modulators of GABAA receptor function [65–67],and as will be discussed, there is a body of literaturesuggesting that melatonin also modulates GABAA receptor

function.To start with, melatonin enhances GABA binding in the

rat brain [80, 139]. Dose–response studies indicate that both

melatonin and diazepam cause maximal enhancement of60% and 70%, respectively, on GABA binding [139].

Melatonin and melatonin analogs bind to GABA receptors[63]. The binding of melatonin and its analogs toGABA receptor-ionophore complexes was studied by the

[35S]t-butylbicyclophosphorothionate (TBPS) radioligandmethod. Melatonin causes allosteric modulation of GA-BAA receptors and the associated chloride ionophorebinding sites for [35S]TBPS similar to that induced by

GABA, barbiturates, and other drugs acting on thebenzodiazepine receptor site [139, 141, 142]. Furthermore,melatonin has been shown to protect benzodiazepine

receptor sites against heat-induced inactivation [139].A direct interaction between melatonin and GABAA

receptors was described by Wan et al. [143], who observed

that melatonin potentiated GABA-evoked current ampli-tude in SCN neurons (which express MT1 receptors) butdecreased GABA-evoked current amplitude in hippocam-pal CA1 neurons (which express MT2 receptors); notably,

these effects were recapitulated by using heterologouslyexpressed GABAA receptors co-expressed with either MT1or MT2 receptors [143], thereby substantiating the original

observations. Similarly, melatonin was found to potentiate5 lm GABAA-evoked currents in cultured chick spinal cordneurons [144]. As the melatonin effects on current ampli-

tude were observed through exogenous application ofGABA to native neurons and HEK293 cells, the changesin current amplitude are necessarily independent of presy-

naptic effects on excitability and transmitter release, andreflect, therefore, an effect on the GABAA receptor itself.An increase in current amplitude in the presence ofmelatonin in the experiments described previously suggests

that melatonin acts as a positive allosteric modulator atGABAA receptors. Additional evidence supporting thisargument is provided by the observation that melatonin

accelerates the decay time of GABA-evoked currents incarp retinal neurons [145]. The melatonin-induced acceler-ation of the current decay time was not blocked by the

melatonin receptor antagonist luzindole [145], again indi-cating that melatonin might act as an allosteric modulatorof GABAA receptors.

Melatonin is synthesized in the pineal gland and, follow-ing pinealectomy, binding of 3H-flunitrazepam (a radiolig-and which binds to the benzodiazepine recognition site inGABAA receptors [146]) decreases, and this decrease is

reversed by exogenously administered melatonin [147, 148].Melatonin also increases hypothalamic concentrations ofGABA by 50% [149]. By using Ro15-1788 (flumazenil), a

selective ligand that acts as an antagonist at the benzodia-zepine recognition site on GABAA receptors [150],numerous studies have demonstrated that various melato-

nin-induced behavioral responses are mediated, in part,through GABAA receptors. The hypothalamic SCN isthought to play a critical role in establishing circadianrhythms [151, 152], and those rhythms are relevant to the

entrainment of normal wake–sleep cycles. Exogenousadministration of melatonin significantly reduces theamount of time required to resynchronize activity and body

temperature following phase-advancement of the light/darkcycle in hamsters, and the effect of melatonin can be blockedby the prior administration of flumazenil [153].

With respect to anesthetically relevant behaviors,flumazenil attenuated or reversed melatonin-induced

Naguib et al.

16

depression of locomotor activity in hamsters [154], melato-nin-induced analgesia in mice [155], and melatonin-inducedanxiolysis in mice [156] and rats [157]. In a similar fashion,

the GABA-receptor blocker picrotoxin antagonized themelatonin-induced increases in total sleep time and slowwave and paradoxical sleep times, and the decreases in timeto sleep onset and wakefulness time [82]. For additional

references, linking GABAergic systems and melatonin, seethe review by Cardinali and Golombek [158]. GABAreceptors in the region of the DMH of rats are implicated

in the control of melatonin release [138]. Application of theGABAA-receptor agonist muscimol to the dorsal hypotha-lamus results in inhibition of melatonin release, whereas

administration of an antagonist, bicuculline, did not affectmelatonin release [138]. Kalsbeek et al. [159] noted that theactivation of SCN neurons induces the release of GABAfrom efferent SCN nerve terminals, resulting in inhibition of

melatonin release by the pineal gland. Taken together, theaforementioned findings indicate that there is a significantinterplay between themelatonergic andGABAergic systems,

and some of the neuropharmacological actions of melatonin(including hypnotic activity) appear to be mediated, via theGABAA receptor and can be blocked with GABAergic

antagonists. The reverse also appears to be true.Melatonin has not been approved by the FDA as a

therapeutic drug. Although it has potential therapeutic

value in operative and critical care settings, no pharmaceu-tical company is realistically interested in developing com-mercial applications of a nonpatentable compound. Theremay, however, be incentive for pharmaceutical companies

to investigate the utility of patentable melatonin analogs.Ramelteon (RozeremTM; Takeda Pharmaceuticals NorthAmerica, Inc., Lincolnshire, IL, USA) is the first melatonin

receptor agonist approved by FDA for treatment ofinsomnia. Although it has a modest efficacy, it representsthe first approved drug acting on systems involved in the

regulation of the sleep–wake cycle. At the molecular level,we are just scratching the surface of understanding howmelatonin works as an anesthetic. The issue is further

complicated by our incomplete understanding of themolecular and cellular mechanism(s) of anesthesia inducedby other intravenous and inhalational drugs and of therelation between anesthesia and sleep circuitry in the brain

[160]. Thus, further work is warranted in defining themechanism(s) of melatonin-induced anesthesia, because ofboth its therapeutic potential as well as the knowledge to be

gained in better understanding its role in regulating sleep/wake cycles.

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