opioid inhibition of rapid eye movement sleep by a specific mu

British Journal of Anaesthesia 1995; 74: 188-192

LABORATORY INVESTIGATIONS

Opioid inhibition of rapid eye movement sleep by a specific mureceptor agonist

A. CRONIN, J. C. KEIFER, H. A. BAGHDOYAN AND R. LYDIC

Summary

Patients receiving opioids report feeling sleepy, butopioids actually inhibit the rapid eye movementphase of sleep (REM). Inhibition of REM sleep isfollowed by a rebound increase in REM sleepassociated with cardiopulmonary complications.The medial pontine reticular formation (mPRF) is abrain region from which morphine can inhibit REMsleep. The present study tested the hypothesis thatspecific subtypes of opioid receptors within themPRF mediate inhibition of REM sleep. Syntheticopioid agonists selective for mu, delta and kappasubtypes were microinjected into the mPRF of fourawake cats and polygraphic recordings of sleep andbreathing were obtained. An enkephalinase in-hibitor was microinjected into the mPRF to assessthe contribution of endogenous opioids to thecontrol of sleep and breathing. Only the mu agonistsignificantly inhibited REM sleep, and no opioiddepressed breathing. These results demonstrate thatopioid-induced REM sleep inhibition is mediatedby mu receptor subtypes in the mPRF. (Br. J.Anaesth. 1995; 74: 188-192)

Key words

Pharmacology, agonists opioid. Sleep. Receptors, opioid. Cat.

Disruption of the sleep cycle and respiratory de-pression are well known but poorly understoodopioid side effects. Despite producing sedation,paradoxically morphine alters the sleep-wake cycleby increasing wakefulness and decreasing rapid eyemovement (REM) sleep [1,2]. Opioid-induced res-piratory depression can be produced by at least twomechanisms: either directly via effects on chemo-sensitive and respiratory nuclei in the central nervoussystem [3,4] or indirectly via sleep-dependentrespiratory depression [5]. REM sleep inhibitionalone does not cause respiratory depression, how-ever, REM sleep deprivation in laboratory animalsand humans is followed by a rebound increasecharacterized by respiratory depression [6-9].

The clinical implications of postoperative REMsleep rebound stem from the fact that the profoundphysiological changes in normal REM sleep aremagnified during REM sleep rebound. Relative towakefulness, REM sleep causes ventilatory de-pression expressed as hypotonia in the upper airway

musculature, hypopnoeas and increased apnoeas [9].During REM sleep there are also episodic car-diovascular changes, including hypertension, tachy-cardia and increased coronary artery blood flow [10].Myocardial stress during REM sleep has been foundto be equivalent to that of maximal exercise in somepatients [11]. In the perioperative period, inhibitionof REM sleep on the first night after operation isfollowed by an intense REM sleep rebound on thesecond and third nights after operation [12]. Thefrequency of hypoxaemic episodes during REMsleep in patients after operation was shown toincrease threefold on the second and third nightsafter operation compared with the preoperative night[8]. Because of the altered physiological regulationduring REM sleep, it is not surprising that numerousclinical reports have correlated cardiopulmonarycomplications specifically with REM sleep rebound[8, 13, 14] and with this postoperative period [15-19].

The brain mechanisms mediating opioid-inducedinhibition of REM sleep are poorly understood. Inthe brain stem, the medial pontine reticular forma-tion (mPRF) is known to play a key role in REMsleep generation [20-22]. Microinjection of mor-phine directly into the mPRF of the intact, un-anaesthetized cat abolished REM sleep [23]. Thismorphine-induced inhibition of REM sleep was site-specific within the mPRF, dose-dependent and wasblocked by administration of naloxone into themPRF. These studies showed that morphine-induced inhibition of REM sleep can be localized toa specific brain region, the mPRF. The dose-dependence and effect of naloxone support the viewthat REM sleep inhibition by mPRF morphine ismediated, in part, by opioid receptors. Morphine isknown to act at mu (u), delta (8) and kappa (K)receptors [24—26]. Thus inhibition of REM sleepcaused by microinjection of morphine into the mPRF[23] could be mediated by subtypes of opioidreceptors. The purpose of the present study was totest the hypothesis that specific opioid receptorsubtypes in the mPRF cause inhibition of REMsleep. Part of this study has been presented inabstract form [27].

ARTHUR CRONIN, MD, JOHN C. KEIFER, MD, HELEN A.BAGHDOYAN, PHD, RALPH LYDIC, PHD, Department of Anes-thesia, Pennsylvania State University, College of Medicine,Hershey, PA 17033, USA. Accepted for publication: September21, 1994.

Correspondence to R. L.

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Mu opioid inhibition of REM sleep 189

Materials and methodsSURGICAL PREPARATIONS FOR PONTINE DRUGADMINISTRATION AND POLYGRAPHIC RECORDINGS

Standard electrodes for objectively quantifying REMsleep, non-REM (NREM) sleep and wakefulnesswere implanted into four adult male cats underhalothane anaesthesia [28] allowing recording of theelectro-oculogram (EOG), nuchal electromyogram(EMG), cortical electroencephalogram (EEG) andfield potentials from the lateral geniculate bodies ofthe thalamus. Bilateral stainless steel microinjectionguide tubes were implanted above the mPRF usingthe stereotaxic coordinates of Berman [29], asdescribed previously [30]. Animals were trained tosleep in the laboratory for 1 month after surgery.When normal sleep patterns were observed, experi-ments were begun.

PONTINE DRUG ADMINSTRATION AND POLYGRAPHICRECORDINGS OF SLEEP AND BREATHING

Unilateral microinjections into the mPRF wereperformed on awake, unmedicated cats by insertinga 31-gauge stainless steel injection cannula into oneof the chronically implanted guide tubes. The opioidagonists microinjected into the mPRF includedthe following: the u agonist DAGO ([D-Ala2,Af-Me-Phe4,Gly-ol5]-enkephalin; 8.95 ug/0.25 ul;69.6 mmol litre"1), the 8 agonist DPDPE (enke-phalin, [D-Pen2-5];3.92 ug/0.50 ul; 11.5 mmol litre"1)and the K, agonist U50488 (trans-( + )3,4-dichloro-N-methyl-iV-[2-(l-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methanesulphate salt; 10.2 ug/0.25 ul; 87.3 mmol litre"1). In addition, one animalreceived three microinjections of kelatorphan(6.45 ug/0.5 ul; 43.4 mmol litre"1), an enkephalinaseinhibitor. This cat subsequently received three largerdoses of kelatorphan (25 ug/1 ul; 84.7 mmol litre"1).Before initiating any opioid studies the accuracy ofguide tube placement was confirmed by micro-injecting the cholinergic agonist carbachol(0.4 ug/0.25 ul; 8.8 mmol litre"1), which produces aREM sleep-like state when administered into themPRF [30-32]. All opioid effects were comparedwith saline (control), previously shown not to altersleep [32] or breathing [22] when microinjected intothe mPRF. Ventilatory frequency was monitored bya nasal thermister. Polygraphic recordings of sleep,wakefulness and respiration were obtained for 2 hafter each mPRF microinjection, in 1-min epochs, aswakefulness, NREM sleep or REM sleep, accordingto standard criteria [28]. Analysis of variance andDunnett's t test were used to test the hypothesis of astatistically significant drug effect on sleep andbreathing.

After completion of the microinjection studies, thecats were anaesthetized deeply with pentobarbitone.The left ventricle was cannulated and the brainperfused with 10% neutral buffered formalin. Thebrain stem was frozen, sectioned at 40-um thickness,and stained with cresyl violet for histological localiza-tion of the microinjection sites.

Results

The drugs administered and the number of injections

(«) were: DAGO (n = 12), DPDPE (n = 18),U50488 (« = 12), kelatorphan (n = 6) and saline(« = 17). These results summarize 7800 minutes ofsleep and 5427 minutes of respiratory recordings.Histological analysis confirmed that the micro-injection sites were in the mPRF, a brain stem regionwhich corresponds to the gigantocellular tegmentalfield, illustrated in detail elsewhere [22, 23, 30-32]and on plate 37 of Berman's atlas [29].

Figure 1 summarizes the effects on sleep andwakefulness of microinjecting opioid agonists intothe mPRF. All drug effects were compared withmicroinjections of saline (control). The u agonistDAGO caused a statistically significant (P < 0.05)increase (71 %) in wakefulness (fig. 1A). Analysis ofvariance revealed no statistically significant effect ofany opioid agonist on the amount of time spent inNREM sleep (fig. 1B). Only DAGO significantly{P < 0.05) reduced the time spent in REM sleep(fig. lc). The 5 agonist DPDPE and the K agonistU50488 had no significant effects on wakefulness,NREM sleep or REM sleep. Kelatorphan had nostatistically significant effect on sleep or wakefulness.

Figure 1 Effea of opioid administration into the mPRF on theamount of time spent in wakefulness (A), NREM sleep (B) andREM sleep (c). Each histogram illustrates the mean (SD)percent sleep-waking state after microinjection of saline(control) and three subtype-specific opioid agonists into themPRF. The number (n) of injections for each drug isindicated. *P < 0.05 compared with saline control.


190 British Journal of Anaesthesia

Table 1 Mean (SD) ventilatory frequency (b.p.m.) during thepolygraphic recordings obtained after microinjection of salineand the three opioid agonists into the mPRF. The number (n)of minutes during which ventilatory frequency was quantified isindicated for each condition

Saline

DAGO

DPDPE

U50488

Wake

23.2(7.1)(n = 403)24.8 (9.3)(n = 386)25.6 (8.6)(» = 495)27.3 (8.6)(n = 472)

NREM sleep

18.2(3.7)(n = 759)18.7 (4.9)(n = 383)18.9(4.1)(n = 940)19.8 (3.9)(n = 666)

REM sleep

27.1 (6.4)(n = 247)26.1 (7.0)(n = 106)28.1 (6.3)(n = 289)27.9(7.5)(n = 281)

As kelatorphan is not an opioid but an enkephalinaseinhibitor [33], the kelatorphan results are not shownin figure 1 which illustrates the effects of the opioidagonists on sleep and wakefulness.

Comparisons of ventilatory frequency acrosssleep-wake states showed that it slowed duringNREM sleep compared with wakefulness and REMsleep (table 1). No opioid agonist significantlydecreased ventilatory frequency below control(saline) values during any sleep-wake state (table 1).

Discussion

This study has shown, for the first time, thatinhibition of REM sleep produced by opioid micro-injection into the mPRF was mediated selectively bythe u receptor subtype. The finding that the uagonist DAGO caused a statistically significantdecrease in REM and an increase in wakefulnesscorresponds closely to the effect of mPRF morphineadministration in cat [23]. The results support thehypothesis that inhibition of REM sleep caused bysystemic opioid administration is mediated, at leastin part, by u receptors in the mPRF. Additionally,the absence of opioid-induced decrease in ventilatoryfrequency suggests that the reduction in the rate ofbreathing caused by systemically administered opioidis not mediated by a single opioid receptor subtypewithin the mPRF.

Enkephalinases rapidly terminate the pharma-cological actions of enkephalins [33]. Intracerebro-ventricular (i.c.v.) administration of the enke-phalinase inhibitor kelatorphan has been shown toenhance analgesia in the rat [33]. Therefore, wewondered if increasing or prolonging the action ofendogenous enkephalins in the mPRF would causeinhibition of REM sleep. In the present study,microinjection of kelatorphan into the mPRF did notinhibit REM sleep. It is not clear if the absence of akelatorphan effect on REM sleep was caused bymethodological differences between the previousreport [33] and the present study. These differencesinclude species (rat vs cat), routes of administration(i.c.v. vs mPRF microinjection), maximum doses(50 ug vs 25 ug) and different dependent measures(analgesia vs REM sleep).

Microinjection studies in the intact, un-anaesthetized cat have demonstrated cholinergiccontrol of REM sleep and breathing by the mPRF[22, 34]. Carbachol, a cholinergic agonist, produces a

REM sleep-like state when microinjected into themPRF [21,30-32]. Conversely, microinjection ofatropine into the mPRF inhibits both natural REMsleep [35] and the REM sleep-like state caused byadministration of carbachol into the mPRF [21, 30].Opioids, because of their ability to inhibit release ofacetylcholine [36, 37], might logically be expected tomodulate cholinergic control of sleep and breathing.Opioid-induced inhibition of release of acetylcholineis dependent on receptor subtype, brain region andspecies. For example, in rabbit hippocampal slices,u, 8 and K agonists inhibited acetylcholine release[38]; in rat striatal slices, only 8 receptor agonistsinhibited acetylcholine release; and in rat frontalcortex, opioids were ineffective [39]. Microdialysisof the mPRF in the barbiturate anaesthetized catshowed a decrease in acetylcholine release whenmorphine was administered systemically [40]. Col-lectively these results suggest that opioid-inducedinhibition of both REM sleep [23] and acetylcholinerelease [40] is mediated by u opioid receptors in themPRF. The ineffectiveness of kelatorphan mayindicate that endogenous enkephalins in the mPRFare not significantly involved in the regulation ofsleep.

In the cat, systemic administration of opioids isknown to cause behavioural excitement. Micro-injection of morphine directly into the mPRF ofintact, unanaesthetized cats inhibited REM sleepwithout causing behavioural excitement or excessivemotor activity [23]. In the present study, pontineadministration of DAGO did not cause excessmovement or behavioural excitement. While thepotential for species-specific effects must be con-sidered, it is clear that the basic and clinicalunderstanding of opioids has been significantlyadvanced by studies on the cat [4].

The mPRF is involved in the regulation of REMsleep [22], but it has not traditionally been regardedas a brain region influencing breathing [41]. Recentfindings, however, have revealed that the mPRF mayalter breathing during sleep [34], particularly res-piratory depression of REM sleep. Ventilatoryfrequency is similar during wakefulness and REMsleep [9] (table 1), but breathing during REM sleepis characterized by a disordered respiratory pattern,decreased minute ventilation, decreased carbon di-oxide responsiveness, decreased upper airway muscletone and decreased discharge of pontine respiratoryneurones [42-44].

By what mechanisms might the mPRF influencebrain stem nuclei controlling breathing? Neuro-anatomical studies showed that the mPRF projectsto, and receives projections from, brain stem res-piratory nuclei and respiratory muscles. Retrogradelabelling of the mPRF by pseudorabies virus in-jection into the posterior cricoarytenoid muscle ofthe larynx demonstrated a multisynaptic pathwaybetween the mPRF and this upper airway muscle[45]. Fluorescent tracing techniques revealed bi-directional pathways between the mPRF and thepontine and medullary respiratory groups [35]. Thusthere are neuronal pathways through which regionsof the mPRF known to regulate sleep can influencebreathing.


Mu opioid inhibition of REM sleep 191

Although sleep has long been known to exacerbateopioid-induced respiratory depression [46], thepresent study demonstrated that the primary effectof microinjecting the u opioid agonist DAGO intothe reticular formation was inhibition of REM sleep(fig. 1) and not depression of ventilatory frequency(table 1). During wakefulness all three agonistsincreased ventilatory frequency. In NREM sleep,DPDPE and U50488 increased ventilatory fre-quency. The mechanisms underlying opioid-induced increases in ventilatory frequency are notknown but similar findings have been reported byothers [4].

The present study supports the conclusion that uopioid receptors in the mPRF mediate opioid-induced inhibition of REM sleep. It is unclear if thisresulted from transduction properties of the ureceptor itself, the relative number of u, 8 and Kreceptors in the mPRF or the binding affinities of theopioid receptor subtypes within the mPRF. Auto-radiographic mapping of opioid receptor subtypes inthe brain stem has been performed [47, 48], but theprecise localization of opioid receptor subtypes inthe mPRF of the cat remains to be determined.

Another potential limitation of the present study isthe concentration of opioid agonists and the potentialfor DAGO to act at 5 and K receptors. It can benoted, however, that DPDPE and U50488 did notproduce DAGO-like effects (fig. 1).

Synergistic or inhibitory interactions betweenreceptors for different opioid subtypes have beendocumented (e.g. the \i-d receptor complex [49]).Thus it is important for future studies to examineinteractions between opioid receptor subtypes withregard to opioid-induced inhibition of REM sleepand respiratory depression. Morphine injected di-rectly into the mPRF caused dose-dependent in-hibition of REM sleep [23]. In addition, futurestudies designed to characterize the dose-responserelationship between DAGO, DPDPE, U50488 andthe amount to which REM sleep is inhibited areadvocated.

This study has clinical implications concerningtwo major opioid side effects for which there is noeffective specific therapy: disruption of REM sleepand respiratory depression. For the anaesthetist, theclinical importance of opioid-induced respiratorydepression is clear [46, 50, 51]. Less obvious, butgaining increasing recognition, is the significance ofopioid-induced inhibition of REM sleep and theintense REM sleep rebound seen after discontinu-ation of opioid therapy [8, 12-14]. The physiologicaleffects of REM sleep, such as episodic tachycardia,hypertension, apnoea and ventilatory depression, arepoorly tolerated by the postoperative patient withimpaired ventilatory function and increased car-diovascular demand.

It is also important to determine the severity ofopioid-induced REM sleep rebound leading toapnoea. Recent epidemiological studies [52] foundthat 9 % of women and 24 % of men have at least fiveepisodes of abnormal breathing during each hour ofsleep and that 2 % of women and 4 % of men have asleep apnoea syndrome. The fact that this prevalencewas observed in a population with no prior diagnosis

of sleep apnoea [52] demonstrates that it is not a raredisease. In the perioperative setting, a more completeunderstanding is needed of the three-way interactionbetween opioid agonists, REM sleep inhibition andcardiopulmonary regulation before any therapeuticintervention can be designed. The possibility existsthat opioid analgesia can be achieved while avoidingdisruption of REM sleep and respiratory depression[53, 54].

AcknowledgementsH.A.B. is supported by grant MH-45361 and R.L by grant HL-40881. We thank Dr B. Roques for kelatorphan and the NationalInstitute for Drug Abuse for DAGO, DPDPE and U50488.

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