PHYSIOLOGY 35: 391– 404, 2020. Published October 14, 2020; doi:10.1152/physiol.00015.

2020
REVIEW
Multi-Level Regulation of Opioid-Induced Barbara Palkovic,1,2
Vitaliy Marchenko,1
Respiratory Depression Edward J. Zuperku,1,3
Eckehard A. E. Stuth,1,4 and
Opioids depress minute ventilation primarily by reducing respiratory rate. This Astrid G. Stucke1,4
1
Medical College of Wisconsin, Milwaukee, Wisconsin; 2Faculty
results from direct effects on the preBötzinger Complex as well as from of Medicine, University of Osijek, Osijek, Croatia; 3Zablocki VA
Medical Center, Milwaukee, Wisconsin; and 4Children’s Hospital
depression of the Parabrachial/Kölliker-Fuse Complex, which provides excit- of Wisconsin, Milwaukee, Wisconsin;
astucke@mcw.edu
atory drive to preBötzinger Complex neurons mediating respiratory phase-
switch. Opioids also depress awake drive from the forebrain and chemodrive.

awake drive; chemodrive; opioids; Parabrachial Nucleus/Kölliker-Fuse Complex;

preBötzinger Complex

Introduction treatment with the opioid antagonist naloxone

Respiration is an automatic process that ensures
adequate oxygen uptake and carbon dioxide re-
moval from the body. The primary drive to breathe
is derived from chemoreception, and respiratory
phase duration and pattern are influenced by feed-
back from lung and airway receptors (110). Auto-
matic breathing is generated in the brain stem and
continues during sleep as well as under sedation
(FIGURE 1). In the awake state, respiration is heav-
ily influenced by the cortico-limbic system of the
forebrain (review in Ref. 44), and respiratory activ-
ity changes promptly with arousal (70), emotions,
and the level of physical activity. Volitional control
allows for breath-holds, hyperventilation, cough-
ing, and complex motor functions like vocalization
(72). Loss of “awake drive” during sleep results in a
decrease in respiratory minute ventilation (49) and
a reduced hypoxic ventilatory response (11, 91,
118).
Opioid-induced respiratory depression (OIRD) is
an important problem in the perioperative period
(84) and increasingly in the community (170). The
respiratory depressant effect is dose-dependent,
and the magnitude of respiratory depression cor-
relates with the level of sedation and analgesia (29,
92). In the clinical setting, opioids can cause mild
sedation, hypoventilation, an increase in PCO2
above 50 Torr, and a decrease in oxygen saturation
already with standard analgesic doses (20, 53, 74,
116a, 165). At that stage, patients can be prompted
to breathe by voice command or touch. With
deeper sedation, painful stimuli are still able to
arouse the patient and elicit respiration. PCO2 can
exceed 60 Torr (20) (53, 74, 165). Very high opioid
doses depress respiration to a degree where nei-
ther severe hypoxia nor hypercapnia nor pain will
be sufficient to generate respiratory efforts (90).
These “overdoses” require artificial ventilation or
(20). The gradual decline in minute ventilation and
the concomitant increase in sedation suggest that
OIRD involves multiple areas in the forebrain and
brain stem.
This review describes the mechanism of respira-
tory rhythm generation in the brain stem, how
excitatory drive from chemoreceptors and the fore-
brain contributes to minute ventilation, and how
these areas are affected by opioids. Since opioids
mostly depress respiratory rate, and apnea results
from an arrest of the respiratory cycle in the expi-
ratory phase rather than from a severe decrease in
respiratory tidal volume (48, 83, 97, 127, 137), we
particularly highlight the mechanism of respiratory
rate control and how it is depressed by opioids. We
focus on in vivo studies that examine respiratory
mechanisms at physiological levels of respiratory
drive, and we present data obtained in human
subjects wherever available.
Organization of the Respiratory
System
Respiratory Rhythm Generation
Respiratory rhythm originates in the ventrolateral
medulla where the neuronal network of the preBötz-
inger Complex and Bötzinger Complex converts
tonic excitatory respiratory drive into a distinct in-
spiratory and expiratory phase (FIGURE 1). Phasic
respiratory activity is relayed via premotor neurons
in the caudal medulla to motoneurons in the spinal
cord. Phrenic motoneurons excite the main inspira-
tory muscle, the diaphragm, whereas thoraco-ab-
dominal motoneurons phasically excite abdominal
muscle activity during active expiration (34, 88, 130).
The neurons of the preBötzinger Complex, the Bötz-
inger Complex, and the adjacent parafacial respira-
tory group can be classified by location, discharge
pattern, neurotransmitters, genetics, and connectiv-
ity (see reviews in Refs. 34, 56, 130, 132). There is

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REVIEW
significant topical overlap between functionally dis-
tinct neuronal populations (5, 140, 172).
Respiratory rhythm generation relies on the activ-
ity of pre-inspiratory neurons to start the inspiratory
phase (“inspiratory on-switch”; FIGURE 1, INSET).
Synchronized activity of a sufficient number of pre-
inspiratory neurons (76) activates other inspiratory
neurons in the preBötzinger Complex to generate a
full inspiratory cycle (2, 34, 50, 104). The level of
excitability of preBötzinger Complex inspiratory neu-
rons is modulated by inhibitory inputs, which affect
the rate of depolarization and the duration of the re-
fractory period (2, 4) (FIGURE 2). Inspiration is termi-
nated when inspiratory neurons are inhibited by post-
inspiratory neurons (“inspiratory off-switch”) (27, 45,
104). Research is ongoing to elicit whether respira-
tory rate is determined mostly by the depolarization
rate of pre-inspiratory and inspiratory neurons in the
preBötzinger Complex (71) or whether it equally de-
pends on the activity of expiratory neurons in the
Bötzinger Complex (7, 104, 132) that inhibit inspira-
tory neurons (71). In addition to neurons contribut-
ing to respiratory phase switching, the preBötzinger
and Bötzinger Complexes also contain inspiratory
and expiratory neurons whose discharge prolongs
phase duration and contributes to inspiratory and
expiratory motor output (tidal volume; FIGURE 1)
(88, 141).
Using comparative cytoarchitecture and immu-
nohistochemistry, Schwarzacher et al. identified

FIGURE 1. Excitatory connections within the respiratory control center and opioid effects
Tonic chemodrive (green solid arrows) is the main excitatory drive to the medullary rhythm generator. A large com-
ponent of chemodrive is routed through the Parabrachial Nucleus/Kölliker-Fuse Complex to phase-switching neurons
in the preBötzinger Complex and determines respiratory rate (dark blue solid arrow). Phasic inputs from the preBötz-
inger Complex activate inspiratory (I) and expiratory (E) premotor and motoneurons (blue dotted arrows). Respiratory
motor output (tidal volume) depends on direct projections from the retrotrapezoid nucleus to preBötzinger Complex
neurons, premotor neurons, and motoneurons. The cortico-limbic system contributes tonic drive to the medullary
rhythm generator (light blue solid arrows). Not shown: direct projections from the motor cortex to phrenic motoneu-
rons as a pathway to override automatic rhythm; projections from the hypothalamus and cerebellum to the medullary
raphe, which may contribute to the state-dependency of respiratory activity. Opioid effects: Parabrachial Nucleus/
Kölliker-Fuse Complex activity was depressed in all studies and at all opioid concentrations. Opioid-induced depres-
sion was also shown for the preBötzinger Complex, the nucleus of the solitary tract, and the medullary raphe. Opioid-
induced sedation suggests depression of forebrain inputs. Premotor neurons are only directly depressed at very high
opioid concentrations. Inset: neuronal subtypes constituting the core of respiratory rhythm generation. Through mu-
tual excitation, network activity of pre-inspiratory neurons (pre-I) in the preBötzinger Complex results in activation of
early inspiratory (early-I) neurons (green arrows). Activity of these neurons is terminated through inhibition by post-
inspiratory neurons (post-I), which themselves are inhibited by early-I neurons during the inspiratory phase (red cir-
cles). Phasic excitation is relayed to inspiratory (I) and expiratory (E) premotor neurons.

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the equivalent of the preBötzinger Complex in the
human ventrolateral medulla (139). Functional
MRI studies showed inspiratory activity in this area
that alternated with expiratory activity in the adja-
cent caudal ventrolateral pons/parafacial group
(63). Interestingly, preBötzinger Complex activity
was increased during loaded inspiration in healthy
controls, whereas patients with chronic obstructive
pulmonary disease, which is associated with im-
paired airflow during expiration, showed increased
activation of the parafacial group (63).
Respiratory Drive
The term “respiratory drive” is used broadly in
respiratory control to describe excitatory inputs to
brain stem areas that increase respiratory activity.
Respiratory chemodrive summarizes the tonic
REVIEW
excitatory inputs to the medullary rhythm gen-
erator that result from activation of chemorecep-
tive brain stem areas and the carotid body (56)
by PCO2 and hypoxia (FIGURE 1). Hypoxia (12)
and hypercapnia (30) cause large increases in
minute ventilation. In humans, this was associ-
ated with increased activity in the carotid body
and the nucleus of the solitary tract (101, 126).
Short episodes of mild hypercapnia also in-
creased activity in the thalamic nuclei, the pon-
tine raphe, the Parabrachial Nucleus/Kölliker-
Fuse Complex, and the locus coeruleus (126). No
additional increase was observed once PCO2 ex-
ceeded ~65 Torr (81).
A large component of respiratory chemodrive
originates in the retrotrapezoid nucleus, which
contains chemosensitive neurons (111, 144, 156),

FIGURE 2. Model of the components determining the membrane potential and illustrating the
effects of changes in excitatory and/or inhibitory inputs
A: model of the components determining the membrane potential (Vm) of a preBötzinger Complex phase-
switching neuron: Vm ⫽ 共gexc·VE兲 ⫹ 共ginh·VI兲⁄共gexc ⫹ ginh ⫹ gleak兲, where gexc is excitatory conductance, VE
is equilibrium potential for excitatory currents, ginh is inhibitory conductance, VI is equilibrium potential for
inhibitory currents, and gleak is leak conductance, e.g., GIRK channels (see text for details). B and C: func-
tional timer model to illustrate the effects of changes in excitatory and/or inhibitory inputs on the neuronal
membrane trajectory (see Refs. 28, 115, 171–173). B: the sum of all excitatory and inhibitory inputs (␴) is
gated to a leaky integrator (LI) at time, t ⫽ 0 s. The magnitude of ␴ determines the rate of the exponential
rise of Vm to a threshold (Thr). Crossing the threshold resets the leaky integrator via a comparator (COM).
The time to crossing the threshold determines the phase duration. C: graphic illustration of the timing op-
eration using the example of rhythmogenic pre-inspiratory neurons. Neuronal discharge in pre-inspiratory
neurons begins when Thr is reached and results in inspiratory on-switch. Inspiratory on-switch terminates
the expiratory phase, i.e., the time to Thr for pre-inspiratory neurons determines expiratory duration (TE).
Due to the nonlinear nature of this mechanism, increases and decreases in ␴ of the same magnitude cause
strikingly different changes in phase duration. Shown are three examples for ␴ (upper) and the correspond-
ing leaky integrator outputs LI (␴) (lower). Setting ␴ ⫽ 1.0 as a baseline reference results in a duration of
TE2 ⫽ 1.6 s (black lines). Increasing ␴ by 40% results in TE1 ⫽ 1 s (red), whereas decreasing ␴ by 40% re-
sults in TE3 ⫽ 5 s (blue). Physiological examples for an increase in ␴ could be an increase in neuronal activ-
ity in the parabrachial nucleus (PBN)/Kölliker-Fuse nucleus (137) or an increase in inhibitory activity during
the preceding inspiratory phase, which shortens inspiratory duration and presumably shortens the post-
inspiratory refractory period (3). The latter could be due to vagal pulmonary stretch receptor input during
lung inflation or increased activity of preBötzinger Complex inhibitory neurons during the inspiratory phase
(3). Decreases in ␴ could be due to a reduction in PBN activity via inhibition of PBN neurons by opioids, by
increases in pulmonary stretch receptor activity during the expiratory phase (173), or by increases in pre-
Bötzinger Complex GABAergic/glycinergic neuronal activity during the expiratory phase (3).

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REVIEW
and also integrates the peripheral chemoreceptive
inputs from the carotid body (55). Individuals with
a genetic lack of chemoreceptive retrotrapezoid
nucleus neurons (congenital central hypoventila-
tion syndrome) suffer from severe hypoventilation
during sleep (129, 161). The retrotrapezoid nucleus
projects glutamatergic excitatory inputs to the
Bötzinger Complex, preBötzinger Complex, Para-
brachial Nucleus/Kölliker-Fuse Complex, and pre-
motor neurons, and phrenic motoneurons (14,
17). Glutamate receptor antagonism in the pre-
Bötzinger Complex results in short, irregular,
low-amplitude breaths and ultimately apnea (25,
113), highlighting the importance of glutamater-
gic drive for respiratory function (FIGURE 3A).
A second chemosensitive system consists of the
neurons of the medullary raphe (see reviews in Refs.
26, 66). Raphe neurons form serotonergic synapses,
at times colocalized with substance P, with neurons
in the preBötzinger Complex and the pontine respi-
ratory group (128). Both neurotransmitters cause a
decrease in membrane potential of preBötzinger
Complex neurons and thus modulate their level of
excitability (128). Input from the raphe obscurus
modulated the pH response of retrotrapezoid nu-
cleus neurons (162). The raphe obscurus receives mul-
tiple synaptic inputs from suprapontine areas (below)
and preBötzinger Complex inspiratory neurons (128),
suggesting that the raphe contributes to state-depen-
dent modulation of respiratory activity (128).
Additional respiratory drive originates in the
cortico-limbic system. In humans, MRI diffusion
tractography established prominent connections
between the hippocampus and the raphe, locus
coeruleus, and nucleus paragigantocellularis lateralis
(42), the human equivalent of the preBötzinger Com-
plex (139). This connection may be responsible for
increasing respiration as part of the “fight-or-flight”
response. Hippocampus and amygdala appear to
mediate the “urge to breathe” during hypercarbia-
stimulated or inspiratory-resistive loaded breathing
(61, 126). In anesthetized rats, stimulation of hy-
pothalamic nuclei increased respiratory rate and
tidal volume (Ref. 158 and review in Ref. 77).
Many of these efferents are relayed by the Para-
brachial Nucleus/Kölliker-Fuse Complex (22),
but some directly project to the spinal cord (21).
The hypothalamus also sends orexinergic projec-
tions to the raphe magnus, raphe obscurus, and
retrotrapezoid nucleus, which do not affect base-
line respiration but enhance CO2 sensitivity dur-
ing the nocturnal active phase in rats (review in
Ref. 114). Direct connections between the motor
cortex and phrenic motoneurons were shown
histologically (133) and functionally (8) in cats.
In humans, functional MRI showed an activation
of the motor cortex with inspiratory loading (Ref.
166, and see review in Ref. 44). Broadly, the
activity of these areas contributes tonic “awake
drive” to the medullary respiratory center (105,

FIGURE 3. Phrenic neurogram tracings obtained in adult decerebrate rabbits in vivo with PCO2
constant
A: antagonism of glutamate receptor function in the preBötzinger Complex (preBötC) through local microinjec-
tion of the AMPA receptor antagonist NBQX (blue) and the NMDA receptor antagonist AP5 (red) caused tachy-
pnea with decreased peak phrenic amplitude, followed by apnea (25). B: antagonism of glutamate receptor
function in the parabrachial nucleus (PBN) and Kölliker-Fuse nucleus (KF) through local microinjection of NBQX
(blue) and AP5 (red) caused severe bradypnea, whereas peak phrenic amplitude was only little decreased.
Complete apnea was never observed (116). Please note the different time scales. C: repeated intravenous bo-
luses of the mu-opioid agonist remifentanil (Remi; 1 mcg · kg–1 · bolus–1) caused increasing bradypnea due to
prolongation of inspiratory and expiratory phase duration. The fourth bolus resulted in apnea (arrow). Remifen-
tanil also substantially depressed peak phrenic activity (123), suggesting an effect on both the PBN/KF and the
preBötC.

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117). Additional awake drive is produced by the
lateral reticular formation of the medulla (117),
emphasizing the state dependency of respiratory
drive.
The periaqueductal gray lies within the tegmen-
tum of the midbrain, at the juncture between the
forebrain and the brain stem. The periaqueductal
gray provides an important connection for sensory
feedback from the nociceptive areas of the spinal
cord and lung mechanoreceptors relaying work of
breathing (23, 24) toward the thalamus (95) and, in
the opposite direction, for drive from the prefron-
tal, premotor, motor, and cingular cortex (33, 96) to
the locus coeruleus, lateral PBN, nucleus ambigu-
ous, and raphe magnus and pallidus (94). It thus
contributes to the integration of the respiratory
pattern, vocalization, and upper airway maneuvers
with changing emotions and behaviors (Ref. 151,
and reviewed in Ref. 153). Stimulation of a subarea
of the periaqueductal gray resulted in tachypnea
(152, 153). This response was significantly reduced
by inhibition of the lateral PBN (62), suggesting
that respiratory drive coming from the periaque-
ductal gray was relayed by the PBN. In cats, activity
of the cerebellar fastigial nucleus did not alter
baseline respiratory rate but increased the re-
sponse to severe hypercapnia and hypoxia (163,
164). Anatomical connections suggest that this ef-
fect is also mediated by the PBN (154).
Multilevel Opioid Effects
The preBötzinger Complex and
Parabrachial Nucleus/Kölliker-Fuse
Complex Are Prime Targets for Drugs That
Depress Respiratory Rate
The concomitant increase of respiratory rate and
tidal volume with hypoxia and hypercapnia may
suggest that both parameters are tightly linked.
However, the parameters can be “uncoupled” by re-
ducing Parabrachial Nucleus/Kölliker-Fuse Complex
activity (39, 41, 47, 89, 116). The Parabrachial
Nucleus/Kölliker-Fuse Complex is an important
relay station for tonic excitatory inputs from the
retrotrapezoid nucleus (142) and the medullary
raphe, as well as from the forebrain, the periaq-
ueductal gray, the cerebellum, and the ascending
nociceptive inputs (73) to the medullary rhythm
generator. In decerebrate rabbits, blockage of glu-
tamatergic inputs to the Parabrachial Nucleus/Köl-
liker-Fuse Complex depressed respiratory rate by
⬎90% but decreased peak phrenic activity only by
⬍20% (116) (FIGURE 3B). Subsequent exposure to
hypoxic hypercapnia during persistent glutamater-
gic block increased respiratory rate only to 25% of
control, whereas peak phrenic activity increased to
160% of control.
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REVIEW
Considering that the respiratory rhythm is gener-
ated in the preBötzinger Complex, a possible expla-
nation for this differential effect is that excitatory
drive to the preBötzinger Complex is not nonspecific,
as depicted in some models (54, 132), but that differ-
ent brain stem areas specifically excite certain neu-
ronal subpopulations (7, 116). Histological and
functional studies have demonstrated excitatory pro-
jections from the retrotrapezoid nucleus to the Para-
brachial Nucleus/Kölliker-Fuse Complex (14, 142)
and preBötzinger Complex (14) and also from the
Parabrachial Nucleus/Kölliker-Fuse Complex to the
preBötzinger Complex (51, 172). The importance of
Parabrachial Nucleus/Kölliker-Fuse Complex activity
for respiratory rate suggests that the majority of ex-
citatory drive to phase-switching neurons in the pre-
Bötzinger Complex/Bötzinger Complex is relayed
through the Parabrachial Nucleus/Kölliker-Fuse
Complex. On the other hand, inputs that determine
respiratory tidal volume likely project directly from
the retrotrapezoid nucleus to neurons in the medul-
lary rhythm generator as well as premotor neurons
and motoneurons in the spinal cord (FIGURE 1).
As described above, inspiratory on-switch de-
pends on the depolarization rate of pre-inspiratory
and inspiratory preBötzinger Complex neurons (4,
5, 18, 19, 171, 172) (FIGURE 2C), whereas inspira-
tory off-switch is likely regulated by the depolar-
ization rate of post-inspiratory neurons (7, 41, 116).
FIGURE 2C illustrates that, when the sum of inputs
(␴) is large, i.e., excitatory inputs (gexc·VE) to a
phase-switching neuron are much higher than in-
hibitory inputs (ginh·VI), the membrane potential
quickly reaches its discharge threshold, and the
duration of the preceding respiratory phase (T) is
short. In this case, a small decrease in excitatory
drive causes only a small increase in phase dura-
tion. In contrast, when the sum of inputs is small,
time to phase-switch is prolonged. Under these
conditions, a decrease in excitatory drive from the
Parabrachial Nucleus/Kölliker-Fuse Complex to
pre-inspiratory neurons or direct inhibition of pre-
inspiratory neurons would substantially prolong
the expiratory phase. Furthermore, a small addi-
tional decrease in excitatory drive or increase in
inhibition would result in a very long expiratory
phase (116) and potentially apnea. This explains
the observation that respiratory rate variation is
greater when excitatory drive to the rhythm gener-
ator is low (19).
Opioids hyperpolarized respiratory neurons
through a mu-opioid-receptor-coupled G-protein-
gated inwardly rectifying potassium (GIRK) con-
ductance (gleak; FIGURE 2A) in the preBötzinger
Complex and Kölliker-Fuse nucleus in vitro (85,
108, 160). Opioids thus have the potential to slow
depolarization of phase-switching neurons in the
preBötzinger Complex either through a direct, inhib-
PHYSIOLOGY • Volume 35 • November 2020 • www.physiologyonline.org 395
REVIEW
itory effect on these neurons or through inhibition of
Parabrachial Nucleus/Kölliker-Fuse Complex neu-
rons, which reduces the excitatory drive to the pre-
Bötzinger Complex.
Opioid Effects on Respiratory Rate and
Motor Output in vivo
Multiple studies point to a direct opioid effect on
preBötzinger Complex neurons. In mice in vivo,
opioids activated a GIRK channel, and block of
GIRK channels in the preBötzinger Complex re-
duced the respiratory depression from systemic
mu-opioid agonists (108). Microinfusion of the
opioid antagonist naloxone into the preBötzinger
Complex completely prevented the 25% respira-
tory rate depression from small doses of IV fenta-
nyl in rats (107). In contrast, in in vivo dogs (112)
and rabbits (145), naloxone injection into the bi-
lateral preBötzinger Complex did not reverse a 50%
respiratory rate depression caused by an intrave-
nous remifentanil infusion; further analysis sug-
gested that the opioid effect on expiratory duration
was mediated mostly outside the preBötzinger
Complex (145). Interestingly, in vitro bath applica-
tion of mu-opioid receptor agonists inhibited in-
spiratory preBötzinger Complex neurons (102, 157)
but did not affect pre-inspiratory neurons (102) or
expiratory neurons (157).
In the in vivo rabbit preparation, naloxone injec-
tion into the parabrachial nucleus partially re-
versed respiratory rate depression from an
intravenous remifentanil infusion from 50% to 20%
(103). In the in vivo decerebrate dog preparation,
microinjected naloxone into the parabrachial nu-
cleus produced a full reversal of remifentanil-
induced bradypnea/apnea (127). In the in situ rat
model, injection of the opioid antagonist CTAP
into the bilateral Kölliker-Fuse nucleus prevented

FIGURE 4. Critical importance of the Parabrachial Nucleus/Kölliker-Fuse complex and preBötzinger

Complex for opioid-induced respiratory depression
A–C: ␮-opioid receptors (Oprm1) were selectively deleted in Oprm1 f/f mice through Cre-virus injection into the pre-
BötC and PBN/KF in this (cohort 1) or reverse order (cohort 2) with 4 –5 wk between injections and plethysmography
recordings (data from A–C from Ref 3, and used with permission from eLife). A: probability density function plot of
the respiratory rate for a representative animal from cohorts 1 and 2 after intraperitoneal morphine (20 mg/kg) or sa-
line before and after Oprm1 deletion in the PBN/KF and preBötC. B: pooled data showed that morphine-induced re-
spiratory rate depression was significantly attenuated after Oprm1 deletion in the preBötC. Oprm1 deletion in both
areas reduced morphine-induced respiratory rate depression from ~50% to ~30%. C: plethysmography recordings in
mice show that Oprm1 deletion in the preBötC ⫹ PBN/KF prevented respiratory rate depression from a very high in-
traperitoneal fentanyl dose (150 mg/kg; right) that usually caused lethal apnea before Oprm1 deletion (left). D: consis-
tent with the murine studies, phrenic neurogram tracings obtained in an adult decerebrate rabbit in vivo show that
sequential microinjections of the opioid antagonist naloxone into the bilateral PBN ⫹ KF and bilateral preBötC re-
versed the respiratory rate depression from intravenous remifentanil infusion (see Ref. 123).

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apnea from systemic fentanyl infusion (137). In
rabbits and rats, respiratory rate depression was
not fully reversed, with local microinjections of
opioid antagonists in the parabrachial nucleus or
Kölliker-Fuse nucleus. The quantitative differences
in the naloxone effects may be due to species
differences.
In freely behaving mice, mu-opioid receptor de-
letion in the bilateral Kölliker-Fuse nucleus re-
duced the respiratory rate depression from small
(10 mg/kg), intermediate (30 mg/kg), and high (100
mg/kg) morphine doses by ~20% at each dose.
Mu-opioid receptor deletion in the bilateral pre-
Bötzinger Complex also reduced respiratory rate
depression after 10 mg/kg morphine; however,
there was no effect at higher morphine doses (160).
In a similar model, mu-opioid receptor deletion in
the preBötzinger Complex attenuated the respira-
tory rate depression from 20 mg/kg morphine from
50% to 70% of control rate (3). Additional attenuation
of the morphine effect from subsequent mu-opioid
receptor deletion in the second area was not statis-
tically significant; however, the study may have been
underpowered to show the effect (3) (FIGURE 4).
Taken together, these studies show that opioid-in-
duced respiratory rate depression results in a large
degree from a combination of direct depression of
the preBötzinger Complex and a decrease in excit-
atory drive from the Parabrachial Nucleus/Kölliker-
Fuse Complex to the preBötzinger Complex. The
depression of each area appears to be dose-depen-
dent and species-dependent.
A recent study in freely behaving rats demon-
strated the existence of a non-opioid-sensitive,
chemo-insensitive respiratory rhythm that devel-
oped after very high opioid doses (300 ␮g/kg fen-
tanyl) (59). Respiratory activity appeared to be
driven primarily by expiratory abdominal efforts
(59). In a different rat model, phasic expiratory
activity was observed even after inspiratory activity
was suppressed by fentanyl (102). Although the
severe hypoxia and acidosis associated with the
high fentanyl dose (58) makes it unlikely that hu-
mans would survive to develop such rhythm, the
study raises the interesting question of whether
opioids also inhibit inhibitory pathways that nor-
mally suppress phasic respiratory activity.
Low doses of systemic opioids that decreased
respiratory rate did not directly depress bulbos-
pinal premotor neurons, although mu-opioid re-
ceptors were present on these neurons (83, 149).
Near-apneic fentanyl doses hyperpolarized pre-
motor neurons, suggesting that high doses di-
rectly depress neuronal activity (57, 83).
Remifentanil infusion depressed phrenic nerve
amplitude more than peak premotor neuronal
activity, suggesting an additional, direct depres-
sant effect of opioids on phrenic motoneurons
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REVIEW
(149). To date, no studies have investigated the
effects of opioids on brain stem mechanisms in
humans.
Chronic opioid use leads to desensitization and
cellular tolerance (86), resulting in increased opi-
oid requirements to maintain the same level of
intended analgesia or euphoria. At the same time,
higher opioid doses may be tolerated before respi-
ratory depression occurs. In freely behaving mice,
chronic exposure to morphine resulted in a de-
crease in respiratory depression from systemic bo-
lus doses of morphine and fentanyl (64). However,
respiratory depression was not reduced at high
fentanyl doses, suggesting only a limited cross tol-
erance between morphine and fentanyl (64). Mul-
tiple clinical studies have highlighted that the risk
of (fatal) overdose in patient populations was in-
creased at higher total opioid doses, suggesting
that chronic opioid use did not eliminate the dose-
dependency of respiratory depression (reviewed in
Ref. 38). There is no evidence that the locations or
network mechanism of OIRD differ between opi-
oid-naive and opioid-tolerant individuals.
Opioid Effects on Respiratory Drive in vivo
In human volunteers, analgesic doses of morphine
decreased the hypoxic ventilatory response (12)
(FIGURE 5A) as well as the ventilatory response to
hypercarbia (30) (FIGURE 5B). This was possibly
due to an effect on the nucleus of the solitary tract:
In anesthetized rats, injection of the mu-opioid
antagonist CTAP into the commissural subnucleus
of the nucleus of the solitary tract almost com-
pletely reversed the depression of the hypoxic ven-
tilatory response caused by intravenous opioids
(169). In the same model, injection of CTAP into
the caudal medullary raphe partially reversed the
depression of the hypercapnic ventilatory response
from systemic opioids (168). In contrast, in in vivo
rats, morphine doses that caused apnea did not
decrease discharge frequency or CO2 response in
chemosensitive retrotrapezoid nucleus neurons
(111).
Opioids also dose-dependently cause sedation,
and this effect reduces or eliminates excitatory fore-
brain inputs to the brain stem (16, 29, 92, 135)
(FIGURE 1). Functional MRI in human volunteers
who received sedative doses of remifentanil showed
decreased activity in the prefrontal cortex, anterior
cingulate, thalamus, subthalamic nucleus, cerebel-
lum, and periaqueductal gray (125), i.e., in areas that
mediate pain and other unpleasant sensations and
that contain a high concentration of opioid re-
ceptors (9). This may explain why already small
opioid doses eliminate the “urge to breathe” dur-
ing breathholds or with inspiratory CO2 chal-
lenges (99, 125). This effect can be clinically
exploited to reduce the sensation of air hunger in
PHYSIOLOGY • Volume 35 • November 2020 • www.physiologyonline.org 397
REVIEW
patients with heart failure (43). It may also ex-
plain why the severe hypoxia and hypercapnia
after opioid overdoses do not cause patient dis-
tress (46).
In anesthetized rats, intravenous morphine in-
hibited acetylcholine release in the prefrontal
cortex and decreased arousal (121). Direct fenta-
nyl injection into hypothalamic subnuclei led to
a decrease in respiratory rate for ⬎20 min (159).
The importance of the cortical arousal state was
shown in patients who received morphine for
postoperative pain control. Respiratory rate was
decreased on average by 8%, and the decrease
correlated with the decrease in beta-1 power in
the electroencephalogram (105) (FIGURE 5, C–E).
In freely behaving rats, 100 ␮g/kg fentanyl—
approximately equivalent to a strong analgesic
dose of 5 ␮g/kg in humans— caused significant
sedation and reduced alpha and beta-2 power in
the EEG recording (106). The increase in theta power
correlated with respiratory rate depression (106). In-
terestingly, opioids did not affect the motor cortex
(125), i.e., as long as patients remain awake, they are
able to breathe on command (84).
The role of respiratory subareas in OIRD de-
pends on the relative contribution of these areas
to respiratory activity as well as on their sensi-
tivity to different opioid concentrations. Until
now, in vivo studies have not differentiated be-
tween these two factors. In addition, more re-
search is needed to determine whether the
opioid effect on any individual area is modified
by changed inputs from other areas. No study to
date has assessed the relative contributions to
OIRD of all factors and all affected areas, i.e.,
chemodrive, awake drive, the Parabrachial Nu-
cleus/Kölliker-Fuse Complex and the preBötz-
inger Complex, in the same model.

FIGURE 5. Contributions of chemodrive and “awake drive” to minute ventilation and opioid effects
A: hypoxic ventilatory response curves in a chloralose-urethane anesthetized cat during control (solid square) and after administration of 0.15 mg/kg
IV morphine. Morphine decreased minute ventilation during hyperoxia but did not change the increase in minute ventilation with hypoxia (see Ref.
12). B: mean ventilatory response to increasing inspiratory carbon dioxide concentrations obtained in 12 male (square) and 12 female (circle) human
volunteers during control (filled) and after 0.1 mg/kg IV morphine, followed by 0.03 mg · kg–1 · h–1 (open). The continuous lines are the linear re-
gression lines through the data points, and broken lines are extrapolated to the apneic threshold. In men and women, morphine decreased minute
ventilation differently: in men by increasing the apneic threshold but in women by decreasing carbon dioxide sensitivity (see Ref. 30). C–E: associa-
tion between respiratory depression from analgesic doses of morphine and loss of “awake drive” per electroencephalogram in pediatric patients.
C: after 0.185 mg/kg morphine, patient 2 presented substantial respiratory rate depression associated with a decrease in ␤1 power. D: in patient 3,
a similar dose (0.178 mg/kg) did not reduce ␤1 power or cause notable respiratory depression. E: in 10 patients, the severity of respiratory rate de-
pression correlated with the intensity of the reduction in ␤1 power (R ⫽ 0.715, P ⫽ 0.02) (105).

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TABLE 1. Studies of opioid and sedative effects in individual respiratory-related areas
Brain Region Mu-Opioid Receptor NMDA Receptor GABAA Receptor
Carotid body 12, 78 65 65, 167
Nucleus tractus solitarii 30, 169 124
Retrotrapezoid nucleus 111 109 87, 155
Medullary raphe 168 10 87
Forebrain 105, 121, 125 93, 120 1, 60, 69, 119
Periaqueductal gray 138
Parabrachial Nucleus/Kölliker-Fuse Complex 3, 85, 103, 137, 160 40, 115 32, 35, 142
Pre-Bötzinger Complex 3, 107, 112, 145, 160 25, 113 15, 27, 98
Premotor neurons 57, 83, 149 80, 134 36, 100, 146, 148
Phrenic motoneurons 68, 149 100 100
Numbers correspond to reference numbers. Bold: where available, we quote “clinically relevant studies,” i.e., in vivo studies that record
respiratory neuronal or global respiratory output during systemic drug application and localized antagonist injection or receptor deletion.
Italic: if such studies are not available, we present in vivo studies recording respiratory-related neurons or global output during localized
application of the sedative agent or the respective receptor agonist or antagonist at clinically relevant or higher concentrations; alternatively,
these are descriptive studies using fMRI or EEG activity in humans. Roman: if no in vivo studies are available, we present in vitro studies
using localized application of the receptor agonist/antagonist or indirect evidence. Sedatives included are NMDA receptor antagonists (e.g.,
ketamine) and GABAA receptor agonists (e.g., Propofol and midazolam). Although clinically relevant opioid concentrations have been
studied in vivo in many areas, this research still needs to be performed for clinically used sedatives.

Future Research
Sedative Drugs
Clinically used sedatives like the alpha-2 antago-
nist dexmedetomidine (78a) and the GABAA-recep-
tor agonist midazolam cause limited respiratory
depression even at high doses, whereas the
NMDA-receptor antagonist ketamine and the
GABAA agonist propofol can cause severe respira-
tory depression and apnea (see review in Ref. 150).
All of these drugs enhance the respiratory depres-
sant effect of opioids (67, 122). Benzodiazepines,
for example, are frequently found in overdose vic-
tims in the community (75). Alpha-2 receptors
have not been identified in the preBötzinger Com-
plex or Parabrachial Nucleus/Kölliker-Fuse Com-
plex, suggesting that any enhancement of OIRD
may be due to removal of “awake drive.” NMDA
and GABAA receptors have been located in all re-
spiratory-related brain stem areas, providing po-
tential targets for sedative agents (25, 27, 36, 37, 41,
79, 98, 113, 115, 158). We hypothesize that seda-
tives affect respiratory rate through the same
mechanism as opioids, i.e., by decreasing neuronal
excitability of phase-switching neurons in the pre-
Bötzinger Complex (FIGURE 2A). The main excit-
atory inputs to preBötzinger Complex neurons are
glutamate receptor mediated (25, 113), whereas
inhibitory inputs are GABAA or glycine receptor
mediated (4, 27). Sedatives that block glutamate-
receptor function or enhance GABAA-receptor
function thus have the potential to decrease respi-
ratory rate, similarly to opioids, either through di-
rect depression of preBötzinger Complex neurons
or through depression of Parabrachial Nucleus/
Kölliker-Fuse Complex activity, which lowers glu-
tamatergic drive to the preBötzinger Complex. This
would explain how sedative doses that cause only
small decreases in membrane excitability and thus
respiratory rate when the drug is given by itself can
result in severe respiratory slowing or apnea when
added after neuronal excitability is already de-
creased by systemic opioids (FIGURE 2C). In addi-
tion, sedatives may depress the activity of other
preBötzinger Complex neurons, premotor neu-
rons, and phrenic motoneurons, and thus contrib-
ute to a decrease in tidal volume. The exact
locations mediating respiratory depression from
sedatives have been studied in far less detail than
opioids (150), and, just as for opioids, the effects on
individual areas may depend on the drug dose
(Table 1).
Respiratory Stimulants
We have described that opioids depress respiratory
activity through effects on multiple areas of the
central nervous system. This is of practical rele-
vance for the development of pharmacological
agents designed to counteract OIRD (see detailed
review in Ref. 31). For example, opioid-induced
depression of the Parabrachial Nucleus/Kölliker-
Fuse Complex significantly reduces excitatory
drive to the preBötzinger Complex. This likely lim-
its the respiratory-stimulating effects of receptor
agonists that specifically stimulate neurons in the
preBötzinger Complex (82, 97). Similarly, opioids
depress areas that relay chemodrive to the respira-
tory center (168, 169). This likely limits the benefit of
drugs that enhance only peripheral chemodrive
(136). Most promising are glutamate receptor mod-
ulators that may increase neuronal activity in many
affected brain stem regions; however, so far, only
AMPA receptor modulators have been investigated
(116a, 131). Likely, the effectiveness of respiratory

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REVIEW
stimulants will always be limited at very high
opioid doses, and their use has to be balanced
with their central nervous and cardiovascular
side effects (31, 52). 䡲
The authors are supported by National Institute of Gen-
eral Medical Sciences Grant R01-GM-112960.
No conflicts of interest, financial or otherwise, are de-
clared by the author(s).
B.P., V.M., E.J.Z., E.A.E.S., and A.G.S. interpreted results
of experiments; B.P., V.M., E.J.Z., and A.G.S. prepared
figures; B.P., V.M., E.J.Z., E.A.E.S., and A.G.S. edited and
revised manuscript; E.J.Z., E.A.E.S., and A.G.S. approved
final version of manuscript; A.G.S. conceived and de-
signed research; A.G.S. performed experiments; A.G.S.
analyzed data; A.G.S. drafted manuscript.
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