Biomedicine & Pharmacotherapy: Shuyuan Yi, Hong Cao, Weilei Zheng, Yin Wang, Peifeng Li, Shoushi Wang, Zhixia Zhou

Biomedicine & Pharmacotherapy 167 (2023) 115472
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha
Review
Targeting the opioid remifentanil: Protective effects and molecular

mechanisms against organ ischemia-reperfusion injury
Shuyuan Yi a, b, c, Hong Cao b, Weilei Zheng b, Yin Wang a, Peifeng Li a, *, Shoushi Wang b, **,
Zhixia Zhou a, *
a
Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
b
Department of Anaesthesiology, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital, Qingdao 266042, China
c
School of Anesthesiology, Weifang Medical University, Weifang 261053, China
A R T I C L E I N F O A B S T R A C T
Keywords: Opioids are widely used in clinical practice by activating opioid receptors (OPRs), but their clinical application is
Opioids limited by a series of side effects. Researchers have been making tremendous efforts to promote the development
Remifentanil and application of opioids. Fortunately, recent studies have identified the additional effects of opioids in addition
Ischemia-reperfusion (I/R) injury
to anesthesia and analgesia, particularly in terms of organ protection against ischemia-reperfusion (I/R) injury,
Opioid receptor (OPR)
Anti-inflammatory
with unique advantages. I/R injury in vital organs not only leads to cell dysfunction and structural damage but
Ca2+ also induces acute and chronic organ failure, even death. Early prevention and appropriate therapeutic targets
for I/R injury are crucial for organ protection. Opioids have shown cardioprotective effects for over 20 years,
especially remifentanil, a derivative of fentanyl, which is a new ultra-short-acting opioid analgesic widely used in
clinical anesthesia induction and maintenance. In this review, we provide current knowledge about the physi
ological effects related to OPR-mediated organ protection, focusing on the protective effect and mechanism of
remifentanil on I/R injury in the heart and other vital organs. Herein, we also explored the potential application
of remifentanil in clinical I/R injury. These findings provide a theoretical basis for the use of remifentanil to
inhibit or alleviate organ I/R injury during the perioperative period and provide insights for opioid-induced
human organ protection and drug development.
1. Introduction tissue responds to reduced blood perfusion for various reasons, which
can cause severe microcirculatory impairment and persistent tissue
Damage to vital organs such as the heart, brain, kidneys, and liver is hypoxia. However, when blood perfusion is restored to the tissue or
one of the leading causes of death in the world and severely affects the organ, cellular dysfunction, and structural damage are not reduced but
patient’s life and prognosis [1]. Acute organ injury occurs mostly in the increased; this phenomenon is called ischemia-reperfusion (I/R) injury.
perioperative period, while chronic injury is mostly caused by long-term I/R injury generally causes acute organ damage [2]. I/R injury can be
irritation and toxic effects. Ischemic injury refers to when an area of attributed to many factors, such as free radical release and continuous
Abbreviations: ADRs, adenosine receptors; AQP, Aquaporins; Bax, BCL-2-associated X protein; BCL-2, b-cell lymphoma; CaMKIIδ, calcium/calmodulin-dependent
protein kinase type II δ; Cav-3, caveolin-3; ERK, extracellular signal regulated kinase; ERS, endoplasmic reticulum stress; FasL, Fas ligand; GPCR, G protein-coupled
receptor; HDAC3, histone deacetylases; HIF-1α, Hypoxia-inducible factor-1α; I/R, ischemia-reperfusion; IL, interleukin; IL-18BP, IL-18 binding protein; iNOs,
inducible nitric oxide synthases; JAK, Janus activated kinase-2; LIF, leukaemia inhibitory factor; MAPK, mitogen-activated protein kinase; miRNAs, microRNAs;
MPTP, mitochondrial permeability transition pore; MTF1, Metal-responsive transcription factor 1; NF-κB, nuclear factor kappa B; NO, nitric oxide; OPRs, opioid
receptors; PDIA3, protein disulfide isomerase A3; PKC, protein kinase C; ROS, Reactive oxygen species; RyR2, ryanodine receptor-2; SOD, superoxide dismutase;
STAT3, signal transducer and activator of transcription-3; TLR4, Toll-like receptor 4; TNF, necrosis factor; TNFR1, TNF receptor 1; ZEB1, zinc finger E-box binding
homeobox 1; ZnT1, Zn2 + transporter 1.
* Corresponding authors.
** Correspondence to: Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao
266021, China.
E-mail addresses: peifli@qdu.edu.cn (P. Li), wangshoushi1226@126.com (S. Wang), zhou_zhixia@qdu.edu.cn (Z. Zhou).
https://doi.org/10.1016/j.biopha.2023.115472
Received 8 June 2023; Received in revised form 4 September 2023; Accepted 7 September 2023
Available online 15 September 2023
0753-3322/© 2023 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de ClinicalKey.es por Elsevier en octubre 12, 2023. Para
uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.
S. Yi et al. Biomedicine & Pharmacotherapy 167 (2023) 115472
lipid peroxidation, cell death due to apoptosis or necrosis, inflammatory protective effect and mechanism of remifentanil on I/R injury in the
cytokines, and microvascular damage [3,4]. There have been several heart and other vital organs. In addition, we further explored the po
efforts to discover new means for the prevention and treatment of I/R tential clinical application of remifentanil as a protective agent for I/R
injury in vital organs, such as ischemic preadaptation, use of specific injury, which provides prospects for future development and drug
drugs to improve organ tolerance to I/R injury, or mitigation of injury. development.
Preconditioning with drugs before ischemia is an important instrument
in preventing I/R injury. Opioids, as important perioperative anes 2. Effects of OPR agonists on I/R injury
thetics, were among the first drugs shown to trigger the preconditioning
cascade [5]. Increasing evidence suggests that opioids may have significant ef
Opioids are widely used in clinical practice by activating opioid re fects on cardioprotection and other organ protection, especially in the
ceptors (OPRs) composed of three major derivatives: μ, κ, and δ [6]. perioperative setting where these drugs are frequently administered
OPRs are broadly distributed in the cardiovascular and central nervous [11]. The traditional OPR system acts in concert with the adaptive stress
systems as well as in peripheral nerves. μ-, δ-, and κ-OPRs are also response and is essential for the active cardiovascular system and other
expressed in organs outside the cardiovascular system (e.g., gastroin physiological activities induced by adaptation [19]. Endogenous and
testinal tract, lung, kidney) [7]. OPRs belong to the G protein-coupled exogenous OPR agonists exert their pharmacological and physiological
receptor (GPCR) family, which converts extracellular stimuli into effects by binding to specific OPRs. In response to stimulation by opioids
cellular signals. After the OPRs are bound, the associated intracellular and other agonists, OPRs activate a series of downstream signaling ki
GPCRs are activated, resulting in reduced neurotransmitter release and nases, including the phosphatidylinositol 3-kinase (PI3K)/AKT and
neuronal excitability. This inference could provide a plausible expla extracellular signal-regulated kinase (ERK) signaling pathways [20]. A
nation for the clinical effects of opioids [8]. In addition to anesthesia number of experimental studies have shown that opioid agonists are
induction and maintenance, opioids are also used in clinical analgesic protective against I/R injury in a variety of organs, such as the heart
treatment for acute pain and cancer pain [9]. However, their clinical [19], brain [21], and intestine [22]. All three major OPRs (μ, κ, and δ)
application is limited by a series of side effects such as respiratory play crucial roles in opioid-induced protection [23]. The pattern of
suppression and addiction. Therefore, researchers have made tremen OPR-mediated organ protective effects is summarized in Fig. 1.
dous efforts in the research and development of Opioids to expand their Preconditioning refers to the application of protective interventions
clinical applications. Fortunately, recent studies have identified the before ischemia, either mechanically (transient ischemia and reperfu
additional effects of opioids in addition to anesthesia and analgesia, sion) or pharmacologically [24]. Postischemic treatment initially refers
particularly in terms of organ protection against I/R injury, which has to the application of protective interventions after reperfusion, a tech
unique advantages, bringing dawn to the development of opioids with nique similar to pretreatment only applied at different times [25]. The
new mechanisms [10–12]. For example, the activation of the OPR sys OPR system positively influences the major determinants of I/R outcome
tem in the heart mediated by opioids promotes the main determinants of (apoptosis, oxidative stress, calcium overload, and inflammation). The
cardiac I/R outcomes, such as infarction/apoptosis, systolic dysfunction, OPR system is also essential for extensively studied pre- and post
arrhythmogenesis, and inflammation. Subsequently, some opioids were processing responses, supporting the important role of OPRs in cellular
confirmed to be candidates for clinical cardiac protection, such as adaptation and tolerance to metabolic disturbances [19].
remifentanil. Opioid-induced cardioprotection has been a hot topic of research in
Remifentanil, a derivative of fentanyl, is an ultrashort-acting opioid recent years. The downstream signaling effectors of opioid-induced
analgesic used during clinical anesthesia. Remifentanil has a high af cardioprotection include ATP-sensitive potassium (KATP) channels,
finity for μ-OPRs and a relatively low affinity for δ- and κ-OPRs [13]. protein kinase C (PKC), tyrosine kinase, PI3K, ERK1/2, mitochondrial
Remifentanil differs from traditional opioids in that it is rapidly permeability transition pore (mPTP) glycogen synthase kinase-3β
metabolized by nonspecific blood and tissue esterases and is not (GSK-3β) and others [23]. Activated PKC acts as an amplifier of pre
dependent on hepatic biotransformation or renal excretion. The unique conditioning stimuli and stabilizes the open state of mitochondrial KATP
pharmacokinetic properties of remifentanil allow for a rapid onset of and myofibrillar KATP by phosphorylation. The opening of KATP ulti
action and short half-life, thus it is widely used in clinical settings [14]. mately leads to cytoprotection by reducing cytoplasmic and mitochon
Remifentanil has a unique position in clinical anesthesia due to its drial Ca2+ overload [26]. The conventional OPR agonist morphine
powerful analgesic and sedative effects. During the induction and reduces the area of myocardial infarction in rabbit hearts. Indeed, low
maintenance of general anesthesia, remifentanil effectively suppresses doses of morphine appear to activate μ-OPRs but not δ- or κ-OPRs [27].
the stress response caused by tracheal intubation and surgical stimula ERK1/2 is activated in response to I/R injury, oxidative stress, and
tion [15]. Remifentanil not only demonstrates strong advantages in hypoxia and plays a key role in the antiapoptotic signaling pathway. The
cardiovascular surgery, but also can be used for anesthesia in various cardioprotective effects of the δ receptor agonist enkephalin are asso
non-cardiac surgeries such as neurosurgery and spinal surgery, and is ciated with increased phosphorylation of AKT and ERK1/2 in the
suitable for various patients, including infants, young children, and the reperfused heart [28]. Endogenous opioid peptides and their receptors
elderly [16,17]. The analgesic effect of remifentanil and its adverse ef are also widely distributed in the central nervous system and exert
fects are dose-dependent and synergistic with other anesthetics, such as physiological effects. Opioids alleviate postischemic injury by attenu
hypnotics, inhalation anesthetics, and benzodiazepines. In recent years, ating inflammatory cell infiltration and proinflammatory cytokine
many clinical and basic studies have confirmed the protective effects of expression in a rat model of stroke [29]. δ-OPR-mediated neuro
remifentanil on a variety of organs. An increasing number of studies are protection is associated with the MAPK signaling pathway [30]. The
focusing on the role of remifentanil in the I/R of the heart, liver, kidney, protective effect of fentanyl against postischemic injury in the heart was
and other organs. It effectively reduces inflammatory responses, acti blocked by A1 adenosine receptor (ADR) antagonists [31]. Selective A1
vates anti-apoptotic signaling pathways, and inhibits oxidative stress. ADR antagonism attenuated the postischemic mechanical function of
The majority of studies assert that remifentanil can attenuate organ I/R the OPR agonist fentanyl in isolated perfused rat hearts, implying
injury through multiple mechanisms. However, several clinical trials crosstalk between opioid and adenosine signaling pathways in the
have also found no effect of remifentanil use on organ I/R injury [18]. I/R-injured myocardium [32,33]. Initial reports of crosstalk between A1
Therefore, further studies on the efficacy and safety of remifentanil for ADRs and OPRs were studied with ventricular myocytes and an isolated
organ I/R are imperative. isovolumic cardiac perfusion model [34]. In addition, the protective
In this review, we provide current knowledge about the physiolog effects of the nonselective OPR agonist morphine and the selective A1
ical effects related to OPR-mediated organ protection, focusing on the ADR agonist preconditioning could be attenuated by the selective A1
Fig. 1. Mechanism model diagram of opioid re

ceptors. Opioid receptor agonism leads to activation of
the PI3K/AKT and PISK pathways (including PKC, PKG,
etc.), activation of the JAK/STAT pathway, ERK, p38,
and corresponding effector molecules such as GSK-3β
are regulated by phosphorylation. Opioid receptors
crosstalk with adenosine receptors and affect cell
membrane KATP, mitochondrial KATP, and mPTP
through multiple signaling pathways. Opioid receptors
regulate intra- and extracellular K+ and Ca2+ concen
trations in cells and mitochondria. The coupled
signaling pathways inhibit apoptosis induced during I/
R by affecting the balance of proapoptotic and anti
apoptotic proteins such as Bax and BCL-2. These opioid
receptor-mediated comprehensive signals constitute a
cytoprotective strategy for anti-cell death and pro-cell
survival.
ADR antagonist and the selective δ-OPR antagonist, respectively [32]. paradox [36]. The mechanisms by which I/R injury occurs have not
This indicates a convergence pathway and/or receptor crosstalk be been fully elucidated, but current studies suggest that calcium overload,
tween OPR- and A1 ADR-mediated cardioprotection, and also suggests abnormal increases in reactive oxygen species, and activation of the
the possibility of OPR/A1 ADR crosstalk in other OPR agonists mediated inflammatory response may be key factors in the occurrence of I/R
ischemia-reperfusion myocardium, such as remifentanil. injury [24]. Through this review, we found that remifentanil can inhibit
At present, the role of remifentanil, which is often widely used in I/R injury through multiple pathways involving the reduction of intra
clinical anesthesia, in organ I/R injury remains controversial. However, cellular Ca2+, anti-inflammation, inhibition of oxidative stress, and
the vast majority of studies support the protective effect of remifentanil apoptosis (Fig. 2).
on organs related to reperfusion injury, and reveal potential mechanisms
involved in multiple molecules and signaling pathways. 3.1.1. Reduction of intracellular Ca2+
Intracellular calcium is mainly stored in mitochondria and the
3. Multiple molecular mechanisms of remifentanil against sarcoplasmic reticulum, and Ca2+ is essential for regulating cellular
ischemia-reperfusion injury function. Intracellular calcium overload during myocardial hypoxia or
ischemia can induce apoptosis, leading to cardiomyopathy and heart
Many clinical and basic experiments have suggested that remi failure. Research has shown that the use of remifentanil alone contrib
fentanil may affect cell proliferation, inhibit apoptosis, alleviate oxida utes to the functional recovery of rat heart after I/R [37]. Remifentanil
tive stress and reduce local inflammatory responses at least through reduces intracellular Ca2+ and ameliorates intracellular calcium over
OPR-mediated signaling pathways, which supports the protective ef load by inhibiting excessive activation of
fect of remifentanil on I/R injury. In addition, the mechanisms by which calcium/calmodulin-dependent protein kinase type II δ (CaMKIIδ) and
remifentanil inhibits I/R injury that was discovered in recent studies ryanodine receptor-2 (RyR2), which has a protective effect on the
seem to provide evidence that it attenuates organ damage and prevents reperfused heart [37]. Remifentanil pretreatment at normal blood
impaired organ function after circulatory recanalization. However, the glucose attenuated hypoxia-reoxygenation (H/R) injury in rat ventric
idea that remifentanil alleviates reperfusion injury in ischemic organs ular myocytes by reducing apoptosis and Ca2+ concentration. However,
seems to be supported more by researchers [35]. After all, a large hyperglycemia attenuates H/R injury and attenuates the protective ef
number of experiments are needed to investigate the protective effect of fect of remifentanil preconditioning in rat ventricular myocytes, which
remifentanil on I/R injury, especially in important organs. may be related to the AKT pathway [38]. The protective effect of hy
perglycemia on myocardial H/R is attributed to its inhibition of the
reduction of anti-apoptotic kinases [ERK, b-cell lymphoma (BCL-2)] and
3.1. Mechanism of remifentanil in inhibiting ischemia-reperfusion injury inhibition of intracellular calcium overload, thereby inhibiting
apoptosis after H/R injury and maintaining cell viability. However,
The occurrence of I/R injury involves several important mechanisms. many in vivo studies have concluded that hyperglycemia is not car
When cells are pretreated with hypoxia or tissues are perfused with dioprotective against I/R [39–41].
hypoxic solutions, cell or tissue damage is more severe after normal
oxygen supply is restored; this phenomenon is called the oxygen
Fig. 2. Mechanisms of remifentanil on ischemia-reperfusion injury. The molecular formula of remifentanil in the middle circle represents the effect of remi
fentanil application on the mechanism of I/R injury. A: Remifentanil inhibits oxidative stress caused by excessive ROS production during reperfusion. Hyperglycemia-
induced oxidative stress impaired the cav − 3-regulated PI3K/AKT and JAK2/STAT3 signaling pathways, which ultimately weakened the protective effect of
remifentanil against cardiac I/R injury. B: Remifentanil reduces intracellular Ca2+ by reducing CaMKIIδ and excessive activation of RyR2 on the endoplasmic re
ticulum, improves intracellular calcium overload, and inhibits cellular injury. C: Remifentanil inhibits the TNF-α/TNFR1, Fas/FasL and JNK signaling pathways,
decreases apoptosis in reperfused organ cells to reduce cell injury, and regulates the expression of the apoptosis-related proteins caspase-3, Bcl, and Bax. D: The
MAPK cascade and NF-κB activation-mediated inflammatory response induced by TLR4 stimulation during reperfusion can be inhibited by remifentanil. β-arrestin2, a
key molecule linking the opioid receptor and TLR4 pathways, inhibits cyclin D1 and ultimately inhibits the release of inflammatory factors. Orange arrows indicate
activation and blue arrows indicate inhibition.
3.1.2. Anti-inflammation (NO)/endothelin-1 balance and inflammatory factor inhibition during

Toll-like receptor 4 (TLR4) stimulates many intracellular signaling hepatectomy in patients with cirrhosis, which is beneficial in reducing
events during IR that ultimately activate the MAPK cascade and nuclear the incidence of hepatic I/R injury and protecting liver function in pa
factor kappa B (NF-κB), thereby inducing an inflammatory response tients [48]. The inhibitory effect of remifentanil pretreatment on the
after reperfusion [42]. TLR4 is thought to mediate inflammatory re inflammatory response in I/R organs is not limited to the liver. Remi
sponses leading to organ ischemia and reperfusion injury. Cytoplasmic fentanil pretreatment also effectively attenuated I/R intestinal mucosal
scaffold and signaling protein β-arrestin2 were demonstrated to be injury in mice and inhibited local oxidative stress and systemic inflam
negative regulators of LPS-induced TLR4 activation [43]. Yang et al. matory responses [47]. Thus, remifentanil can reduce the inflammatory
demonstrated that remifentanil pretreatment inhibited TLR4 expression, response in I/R organs by promoting iNOs and inhibiting TLR4-related
reduced inflammatory responses in I/R livers, and achieved protective signaling pathways.
effects against hepatic I/R injury through upregulation of β-arrestin2
expression. β-arrestin2 may be a key factor linking the OPRs and TLR4 3.1.3. Antioxidative stress
pathways [44]. The β-arrestin2/ERK/cyclin D1 axis mediates the effect Reactive oxygen species (ROS) are a class of oxygen-containing
of remifentanil on liver regeneration in mice after major hepatectomy metabolites formed by oxygen that are chemically more active than
[45]. Inflammatory cytokines play a crucial role in myocardial I/R basal oxygen. In pathological conditions such as I/R, excessive pro
injury, and remifentanil negatively regulates the TLR4/NF-κB signaling duction of reactive oxygen species or insufficient antioxidant capacity of
axis to inhibit the levels of inflammatory cytokines such as interleukin the body may trigger oxidative stress [49]. Zhang’s team found that
(IL)− 1β, tumor necrosis factor (TNF)-α, and IL-8 [46]. microRNAs (miRNAs) involved in remifentanil provide benefits to
In another study, remifentanil was found to inhibit the inflammatory myocardial I/R injury by inhibiting the inflammatory response and
response in the reperfused liver by promoting the expression of induc oxidative stress [46]. Remifentanil significantly increased the levels of
ible nitric oxide synthases (iNOs) [47]. iNOs may mediate the protective superoxide superoxide dismutase (SOD) and glutathione in myocardial
effect of remifentanil pretreatment on hepatic I/R injury by depleting I/R rats, while decreasing the levels of malondialdehyde, suggesting that
reactive oxygen species and promoting endogenous nitric oxide pro remifentanil can reduce oxidative stress and attenuate myocardial I/R
duction to attenuate the inflammatory response, rather than through injury [46]. Remifentanil upregulated miR-206–3p levels to negatively
OPRs. Clinical studies have also found that propofol combined with regulate the TLR4/NF-κB signaling axis, improving cardiac function and
remifentanil anesthesia contributes to the nitric oxide inhibiting oxidative stress in myocardial I/R injury [46]. Increased
oxidative stress increases cellular structural damage and dysfunction or endoplasmic reticulum homeostasis and induces endoplasmic reticulum
even cell death. The pathogenesis of myocardial I/R injury in patients stress (ERS) [66,67]. It has been demonstrated that remifentanil in
with diabetic is complex, and hyperglycemia-induced oxidative stress is creases histone H3 acetylation and ultimately protects H9c2 car
one of them [50]. It has been demonstrated that excessive oxidative diomyocytes from H/R injury by decreasing ERS-related apoptosis and
stress may reduce the tolerance of diabetic hearts to myocardial I/R histone deacetylase (HDAC) expression [68]. The protective effect of
injury [38]. Diabetes mellitus induces fundamental alterations in remifentanil in inhibiting endoplasmic reticulum stress and I/R cardiac
cellular signaling cascades, which in turn affects the progression of I/R injury may be related to the inhibition of metal-responsive transcription
injury and response to cardioprotective intervention [51]. Thus, it can Factor 1 (MTF1) and Zn2+ transporter 1 (ZnT1) expression, which can
be hypothesized that hyperglycemia-induced oxidative stress may maintain Zn2+ homeostasis [69]. p38 MAPK is a member of the MAPK
contribute to the impaired cardioprotective function of remifentanil. family and can be activated by intestinal I/R. Remifentanil can also
Hyperglycemia-induced oxidative stress plays an important role in the inhibit intestinal I/R-induced oxidative stress and ERS by activating p38
development and progression of ischemic heart disease. Therefore, MAPK [70].
diabetic patients are more susceptible to I/R injury during the restora
tion of oxygen supply to ischemic myocardium compared to normo 3.1.5. Others
glycemic patients. Caveolin-3 (Cav-3) is a major isoform of the caveolin Autophagy is a highly conserved catabolic cellular process that al
family that forms cardiomyocytes providing a platform for enriching lows the degradation and reuse of long-lived proteins and damaged
cardioprotective signaling molecules [52]. OPRs have been shown to organelles. Experimental studies have shown that autophagy plays
promote cardioprotection in cardiomyocytes in a caveolae-dependent different roles during ischemia and reperfusion. During reperfusion,
manner [53]. Cav-3 is crucial for myocardial tolerance to I/R injury large amounts of reactive oxygen species upregulate Beclin1 expression,
and is also required to mediate cardioprotection provided by opioid which further activates autophagy and leads to cell death [67,71,72].
pretreatment [54]. The cardioprotective effect of remifentanil can be Posttreatment with remifentanil enhances autophagy in H/R-activated
abrogated by hyperglycemia-induced oxidative stress, and this process is cells and promotes autophagic flux [73]. Myocardial edema can
associated with impairment of cav-3-regulated PI3K/AKT and initiate myocardial apoptosis and lead to myocardial I/R injury. Aqua
Janus-activated kinase-2 (JAK)/signal transducer and activator of porins (AQP), a family of proteins that act as water channels, are one of
transcription-3 (STAT3) signaling [55]. Increased oxidative stress in the drug targets to reduce somatic edema. It has been found that the
cells may interfere with their function, promote apoptosis, and even be AQP1 inhibitor acetazolamide enhances the infarct size reduction by
cytotoxic. remifentanil posttreatment [74]. In addition, hypoxia may promote ROS
In addition to blood glucose concentration, the protective effect of production and oxidative stress-mediated biomolecular damage. Remi
remifentanil on ischemic myocardium is also related to the duration of fentanil pretreatment reduced the level of hypoxia-mediated protein
administration and the dose administered. Short-term exposure to high carbonylation and protected human cardiomyocytes from
doses of remifentanil increases cellular oxidative stress, exacerbates hypoxia-induced cellular senescence and necrosis [75].
myocardial I/R injury, and causes some damage to DNA [56]. Hypoxia-inducible factor-1α (HIF-1α) is involved in various biological
ROS-mediated reperfusion injury is capable of inducing acute and processes such as glycolysis, cellular hypoxic survival, and angiogenesis.
chronic rejection. After uterine I/R injury, remifentanil application re Stabilization of HIF-1α attenuates hepatic I/R injury [76]. One study
duces the level of histopathological damage and oxidative stress and found that remifentanil upregulated HIF-1α expression, promoted zinc
increases the activity of the antioxidant enzymes catalase and SOD [57]. finger E-box binding homeobox 1 (ZEB1), and inhibited leukemia
inhibitory factor (LIF), thereby alleviating hepatic I/R injury [77].
3.1.4. Activation of anti-apoptotic pathways of survival
Diabetes attenuates any protective effect in remifentanil 3.2. Ischemia-reperfusion injury in many vital organs is alleviated by
pretreatment-induced myocardial I/R injury, which may be associated remifentanil
with I/R leading to a reduction in the recovery of anti-apoptotic
pathway-related protein activity and abnormal sarcoplasmic reticulum Many opioids have been widely demonstrated to have beneficial
gene expression [58]. In the diabetes rat model, remifentanil pretreat effects on a variety of organ I/R injuries. The organ-protective effects of
ment increased the expression of ERK1/2 and the anti-apoptotic protein remifentanil, an ultrashort-acting opioid analgesic, have become a hot
BCL-2, and decreased the expression of the pro-apoptotic protein Bax topic of research in recent years. A large number of basic studies support
and cytochrome c [58]. The protective effect of remifentanil on the idea that remifentanil administered before or after reperfusion re
myocardial I/R injury has been demonstrated in many experiments to be duces I/R injury in a variety of organs, including the heart [78], liver
associated with anti-apoptotic mechanisms. Remifentanil not only [79], brain [21], kidney [80], and intestine [81]. This view provides a
ameliorated myocardial I/R-induced cardiomyocyte injury and rationale for the use of remifentanil as an analgesic with additional
improved cardiac function in rats but also decreased the expression of organ-protective benefits in the clinical setting. However, there are also
the apoptosis-related protein cleaved caspase-3 and its mRNA and clinical studies that suggest that the application of remifentanil does not
increased Bcl/BCL-2-associated X protein (Bax) in cardiomyocytes [59, significantly contribute to organ reperfusion injury. To date, studies on
60]. The Fas/Fas ligand (FasL) signaling pathway is also involved in remifentanil-induced preconditioning or posttreatment have been pre
remifentanil-mediated inhibition of apoptosis, oxidative stress, and in dominantly conducted in the heart, brain, intestine, liver, and other
flammatory responses in I/R cardiac myocytes [61]. The protective ef organs. Fig. 3 summarizes the effects of remifentanil on I/R injury in
fect of remifentanil pretreatment on I/R hearts is closely related to the various vital organs and the changes in related pathways and cytokines.
activation of c-Jun NH2-terminal kinases (JNK) and ERK anti-apoptotic
pathways [62,63]. In an I/R rat brain injury model, remifentanil pre 3.2.1. Heart
treatment may prevent I/R brain injury by inhibiting exogenous Cardiac I/R injury is very common in clinical practice and is
apoptotic signaling pathways induced by TNF-α/TNF receptor 1 frequently seen in the treatment of coronary artery disease, heart attack,
(TNFR1) and the JNK signaling pathway [64]. Remifentanil posttreat cardiomyopathy, or during heart transplantation [82–84]. In recent
ment also attenuates apoptosis of myocardial H9c2 cardiomyocytes after years, there has been much interest in the efficacy of opioids in pre
H/R injury by downregulating targeting GSK-3β [65]. venting or treating cardiac I/R injury. Myocardial ischemia results in
The endoplasmic reticulum is a target of myocardial I/R injury and increased synthesis and release of opioid peptides in cardiomyocytes,
an effector of several cardioprotective strategies. In ischemic myocardial and by acting on OPRs to counteract the release of high catecholamines,
tissue, disruption of oxygen and blood has detrimental effects on it may reduce cardiomyocyte injury and protect cardiomyocytes [59,
Fig. 3. Many important organs are protected from ischemia-reperfusion injury by remifentanil. Remifentanil inhibits or alleviates the ischemia-reperfusion
injury by regulating different key signal pathways and genes in multiple organs, including heart, intestine, brain, kidney, and uterus. Yellow arrows represent
upregulation or promotion, and green arrows represent downregulation or suppression.
85]. Given the increasing use of remifentanil for general anesthesia for independent of the time and duration of administration [62]. Several
cardiac or noncardiac surgery, it is important to understand whether studies have suggested that different concentrations of remifentanil
remifentanil provides cardioprotection. It is now generally accepted that have a protective effect on I/R myocardium and that it can improve
remifentanil attenuates cardiac I/R injury and achieves cardioprotective myocardial pathological injury by targeting IL-18 to reduce INF-γ,
effects through multiple mechanisms [35]. Clinical studies have also TNF-β, and IL-1β mRNA and increase IL-18 binding protein (IL-18BP)
found that the use of remifentanil in anesthetic protocols reduces protein expression in I/R myocardium [97]. However, Mei et al. found
myocardial injury from extracorporeal circulation [86]. that the protective effect of remifentanil on cardiomyocytes was
Cardiac I/R injury often induces cardiomyocyte apoptosis, leading to impaired at very high doses [56]. This difference may be due to different
further deterioration of cardiac function [87–89]. Therefore, inhibiting drug concentration settings and different mechanisms of myocardial
cardiomyocyte apoptosis and improving cardiomyocyte survival have pathological damage.
become important goals in alleviating cardiac I/R injury [90]. Corre In addition to pretreatment, both remifentanil posttreatment and
spondingly, these also appear to be one of the important mechanisms by continuous infusion can have beneficial effects on cardiac I/R injury
which remifentanil protects the heart from I/R injury [59,61,63]. [98]. However, continuous infusion of remifentanil may attenuate the
Cellular senescence and necrosis due to hypoxia in human cardiac protective effect of ischemic preconditioning on ischemic myocardium.
myocytes can also be inhibited by remifentanil pretreatment [75]. The reason for the difference in efficacy between short-term and
GSK-3β is a key downstream effector of remifentanil pretreatment car continuous infusion of remifentanil may be due to the continued pres
dioprotection. Remifentanil pretreatment can protect the I/R myocar ence of remifentanil leading to receptor desensitization and/or
dium by activating JAK2/STAT3 signaling and ultimately inhibiting down-regulation, which impairs the ability of endogenous opioids to
GSK-3β [91]. Cardiac microvascular endothelial cells are also protected cope with I/R injury [99]. This will be an important factor to consider
by remifentanil during H/R. Remifentanil enhanced the migratory ca for long-term infusion of remifentanil. Endogenous opioid-like sub
pacity and tubular structure formation of H/R-stimulated microvascular stance expression is increased in cardiac tissue before and after infarc
endothelial cells in a concentration-dependent manner and ameliorated tion [100]. Activation of opioid-like substance receptor subtypes
H/R-induced cellular dysfunction by modulating the PI3K/AKT/HIF-1α enhances ischemic tolerance. Cardiac μ-OPR expression is increased
signaling pathway [92]. As an OPR agonist, remifentanil can also during the development of chronic heart failure, and μ-OPRs provide
stimulate cardioprotective effects by acting on OPRs. Remifentanil cardioprotection mainly through the ERK/GSK-3β signaling pathway
produces a delayed cardioprotective effect similar to ischemic pre [101]. The extent of protection against cardiac I/R injury by remi
conditioning through all three OPRs [78]. However, δ-and κ-receptors fentanil posttreatment is similar to that of ischemic posttreatment, and
may play a major role in remifentanil preconditioning and ischemic this protection is associated with κ- and δ-receptors [102]. During the
preconditioning-mediated cardioprotection. Extracardiac μ-receptors reperfusion phase, remifentanil posttreatment has crosstalk with ADRs
are also involved in the cardioprotective effects of remifentanil [93,94]. in I/R myocardium [78]. Meanwhile, A1 and A2 ADRs crosstalk with
Further studies have shown that remifentanil and other OPR agonists OPRs during remifentanil pretreatment [103]. Application of remi
not only have direct cardiac protective effects, but also enhance ROS- fentanil treatment after H/R in H9c2 cardiomyocytes attenuated cell
mediated cardioprotection [95]. Beyond that, the dose effect of remi injury, reduced the level of apoptotic proteins produced in response to
fentanil on myocardial I/R damage remains controversial. Both remi H/R and enhanced cellular autophagy [73].
fentanil pretreatment and ischemic pretreatment protect the Many studies have found that the protective effect of remifentanil
myocardium through PKC activation mechanisms [96]. Many studies against cardiac I/R injury may be impaired in certain pathologies such
support that the protective effect of remifentanil on I/R myocardium is as diabetes/hyperglycemia [38,58,104]. One aspect of the weakening of
remifentanil’s cardioprotective effect by hyperglycemia may be related studies because some drugs or operations used during surgery and
to the enhanced oxidative stress that impairs the signal pathway regu anesthesia also affect myocardial function. One study found no signifi
lated by cav-3 [55]. On the other hand, hyperglycemia causes a decrease cant difference in postoperative adverse outcomes between isoflurane
in antiapoptotic kinases (ERK, BCL-2), inhibits intracellular calcium anesthesia and propofol combined with remifentanil in patients under
overload, and suppresses apoptosis after H/R injury [38]. Some studies going coronary artery bypass grafting without extracorporeal circula
have also shown that, the protective effect of remifentanil posttreatment tion [18]. Lin et al. found that remifentanil posttreatment also inhibited
on H/R injury in normoglycemic cardiomyocytes is at least partially I/R myocardial edema by inhibiting the function of AQP1 [74]. In
mediated through apoptosis induced by endoplasmic reticulum stress conclusion, studies to date suggest that remifentanil is a very promising
[104]. Hyperglycemia, however, attenuates the cardioprotective effect agent for the prevention of I/R injury in the heart or other organs
of remifentanil posttreatment [104]. These studies indicate that the (Table 1).
physiological state of organism or organ function may affect the pro
tective effect of remifentanil on organ I/R injury. 3.2.2. Brain
In actual clinical settings, the protective effect of remifentanil on I/R Cerebral ischemia is one of the most serious diseases that endanger
hearts when combined with other anesthetic drugs can differ from basic human health. Cerebral ischemia often leads to neuronal death and
Table 1
Effects of remifentanil on cardiac ischemia-reperfusion injury.
Experimental models/ Administration dose Cardiac status Function Related pathways or genes Refs
cell types
Rat 20 μg/kg/min, in vivo Normal, I/R Protecting ↑ κ- OPRs, δ- OPRs [102]

Rat 100 ng/ml, in vitro Isolated heart, I/R Protecting ↑ ERK1/2 phosphorylation [78]
Rat 0.1 μmol/L, in vitro Isolated chronic heart Protecting ↑ ERK and GSK-3β phosphorylation [101]
failure, I/R
Rat 3 nM, in vitro Isolated heart, I/R Protecting ↓ p-RyR2 and CaMKIIδ [37]
Rat 100 ng/ml, in vitro Isolated heart, I/R Protecting NM [98]
Rat 6 μg/kg/min, femoral vein Diabetic, I/R Protecting ↑ ERK1/2, Bcl-2, SERCA2a, PLB [58]
phospholamban, RyR2, calsequestrin;
↓ Bax and cytochrome C
Rat 3 nM, in vitro Isolated heart, I/R Protecting with ROS NM [95]
H9c2; Cardiomyoblasts 1 mM, in vitro Normal, H/R Protecting ↑ LC3II [73]
H9c2; Cardiomyoblasts 1 mM, in vitro Normal, H/R Protecting ↑ GSK-3β; [65]
↓ HDAC3
Rat 6 μg/kg/min, i.v. Diabetic, I/R The protective effect is ↑ PI3K/AKT, JAK2/STAT3 [55]
inhibited by diabetes
Rat 20 μg/kg/min, 15 min, 1 h, 2 h, Normal, I/R The protective effect is NM [56]
in vivo inhibited by high dose
Neonatal rat; Ventricular 1 mM, in vitro Hyperglycemia, H/R The protective effect is In normoglycemia, ↑ Bax; [38]
myocytes inhibited by Hyperglycemia ↓ caspase-3, AKT, ERK1/2, Bcl-2
H9c2; Cardiomyoblasts 0.1, 1, 10 mM, in vitro Hyperglycemia, H/R The protective effect is In normoglycemia, [104]
inhibited by Hyperglycemia ↓ caspase-3, capase-12, CHOP, GRP 78
Rat 10 μg/kg, 30 min, in vivo Normal, I/R Protecting ↓ AQP1 [74]
Rat 1.8 μg/kg/min, 0.6 μg/kg/min, in Normal, I/R Protecting ↑ Bcl-2/Bax; [59]
vivo ↓ cleaved-3
Rat 50 mg/ml, i.v. Normal, I/R Protecting ↓ Fas/FasL [61]
Rat; H9c2; 100 ng/ml, in vitro; Isolated heart, I/R; Protecting ↓ MTF1, ZnT1, ROS [69]
Cardiomyoblasts 20 μM, in vitro Normal, H/R
Rat 0.4, 2, 10 μg/kg/min, in vivo, Normal, I/R Protecting ↑ IL-8BP; [97]
gavage ↓ IL-18, INF-γ, TNF-β, IL-1β
Rat 6 μg/kg/min, jugular vein Normal, I/R Protecting ↓ PKC [96]
Rat 1, 5, 10, 20, μg/kg/min, in vivo Normal, I/R Protecting ↑ κ- OPRs, δ- OPRs, μ-OPRs [78]
H9c2; Cardiomyoblasts 1, 10 μM, in vitro Normal, H/R Protecting ↑ histone H3 deacetylation; [68]
↓ GRP78, cleaved caspase-12, cleaved
caspase-3, HDAC3, CHOP
Primary human cardiac 4, 6, 8 ng/ml, 24 h, in vitro Normal, Hypoxia Protecting ↑ MLKL； [75]
myocytes ↓ HIF-1α, HSP 90, p21, IL-18
Rat 6 μg/kg/min, in vivo; Normal, I/R; Protecting ↑ JAK2/STAT3; [91]
100 ng/ml, in vitro Isolated heart, I/R; ↓ GSK3, cleaved caspase-3
Rat ventricular myocytes 0.1, 0.3, 1, 3, 10 μM, in vitro Normal, H/R Protecting ↑ δ-OPRs, AKT, ERK [93]
Rat 0.2, 0.6, 2, 6, 20 μg/kg/min, Normal, I/R Protecting ↑ κ- OPRs, δ- OPRs, μ-OPRs [60]
jugular vein
Microvascular 0.625, 1.25, 2.5 µm, 1 h, in vitro Normal, H/R Protecting ↑ PI3K/AKT/HIF-1α [92]
endothelial
Rat 6 μg/kg/min, in vivo Normal, I/R Protecting ↑ ERK1/2, Bax; [62]
↓ Bcl-2, cytochrome C
Rat 30 μg/kg, i.p. Normal, I/R Protecting ↑ miR-206–3p; [46]
↓ TLR4, NF-κB
Rat; 20 μg/kg/min, jugular vein; Normal, I/R; Protecting ↑ PINK1; [60]
Primary 1, 5, 10 μM, in vitro Normal, H/R ↓ mir-205, caspase-3
cardiomyocytes
Rat 100 ng/ml, in vitro Isolated heart, I/R Protecting with ADRs ↑ OPRs, ADRs [103]
Rat 25, 50, 100 μg/L, in vitro Isolated failing heart, I/ Protecting ↑ JNK, ERK1/2, GSK-3β, Bcl-2/Bax [63]
R
Rabbit Transient 16 μg/kg/min; continuous Normal, I/R Protecting NM [99]
3–10 μg/kg/min, ear vein
NM, Not mentioned; i.v., intravenously inject; i.p., intraperitoneally inject
causes irreversible brain damage, resulting in neurological dysfunction upregulating β-arrestin2 to inhibit the expression of TLR4. Thus,
or even death. Early restoration of blood flow is an important means to β-arrestin2 may be a key molecule linking the μ-OPRs and TLR4 path
prevent cerebral I/R injury. Pharmacological preconditioning to in ways [44,45].
crease the tolerance of brain tissue to I/R injury is also an important IL-18 is an important proinflammatory cytokine that acts as a
means of prevention [5,64]. Endogenous opioids and their receptors are modulator of the immune response, initiating a cascade of responses to
widely distributed in the central nervous system and exert nociceptive or many inflammatory cytokines, such as TNF-α and IL-1β. The activity of
analgesic effects [105]. Remifentanil reduces neurological damage IL-18 is mainly regulated by its natural inhibitor IL-18BP, which binds
scores and infarct size after brain I/R injury at clinical concentrations IL-18 with high affinity, effectively blocking its binding to the receptor
and is protective against focal brain I/R injury in rats. This protective and inhibiting the inflammatory response [112,113]. In normal liver
effect may be related to activation of δ-OPRs and inhibition of ERK1/2 tissues, remifentanil upregulates hepatic IL-18BP expression through
and TNF-α [21]. TNF-α/TNFR1 and JNK signaling pathway-induced transcriptional activation of IL-18BP [114]. In I/R liver tissue, naloxone
exogenous apoptotic signaling also mediate the preventive effect of inhibited remifentanil-mediated downregulation of IL-18 without
remifentanil on brain I/R injury [64]. Remifentanil pretreatment elevating IL-18BP and significantly attenuated its protective effect on
significantly improved cognitive function and reduced infarct size in hepatic I/R [115]. This would suggest that remifentanil is protective
brain tissue of brain I/R rats. against hepatic I/R injury by inhibiting the inflammatory response at
Postischemic recanalization application of remifentanil has also been least partially through OPRs. In addition to suppressing serum inflam
shown to have neuroprotective effects. Remifentanil post-adaptation matory cytokine concentrations, remifentanil pretreatment mediates
significantly attenuated spatial learning ability and neurological death hepatoprotection by reducing neutrophil accumulation in ischemic liver
in the hippocampal CA1 region induced by whole brain I/R injury in tissue [47].
rats, and the mechanism may be related to the effect of anti-apoptotic In addition to inhibiting the inflammatory response, the protective
signaling through the PI3K pathway [106]. Therefore, the protective effect of remifentanil against I/R liver injury is also associated with a
effect of remifentanil on brain I/R injury may be related to its inhibition reduction in hepatocyte apoptosis through the activation of anti
of neuronal apoptosis. One retrospective study found that in 4502 apoptotic pathways. A study by Zhao et al. found that the beneficial
craniotomy patients undergoing clipping of intracranial aneurysms, the effects of remifentanil pretreatment to inhibit I/R liver tissue may be
use of remifentanil reduced in-hospital mortality [107]. The use of mediated through multiple signaling pathways, including mitochondrial
remifentanil significantly reduced serious complications and improved integrity, oxidative stress, and inflammatory responses [79]. Remi
prognosis after cerebral I/R. fentanil also ameliorates liver reperfusion injury by upregulating HIF-1α
expression, promoting ZEB1, and inhibiting LIF expression [77]. Remi
3.2.3. Intestine fentanil has a molecular structure that allows it to penetrate the
Intestinal I/R injury occurs frequently in clinical settings, such as blood-brain barrier and act by binding to OPRs in the central nervous
extracorporeal circulation, organ transplantation, trauma, and neonatal system. Microinjection of remifentanil into the dorsal vagal complex
disease. Intestinal I/R injury not only impairs mucosal absorption of reduces serum transaminases, inflammatory cytokines, liver tissue
nutrients but also damages the integrity of the mucosa, leading to bac damage, and apoptosis. These effects are not eliminated by the μ-OPR
terial invasion and systemic inflammatory responses [108]. Effective blocker naloxone but by peripheral hepatic vagotomy. Thus, the central
measures and drugs to protect the intestine from I/R injury are still vagal pathway, but not the peripheral μ-OPRs, is primarily involved in
lacking. Remifentanil pretreatment inhibits IL-6 production and thereby the protective effects of remifentanil pretreatment on hepatic I/R [116].
suppresses the systemic inflammatory response and attenuates intestinal Clinical trials have also demonstrated the protective effect of intra
I/R injury in mice [81]. Hale et al. found that remifentanil not only operative application of remifentanil on the liver in I/R. In patients
attenuated the intestinal I/R-induced reduction in intestinal contrac undergoing liver cancer surgery, remifentanil better maintained hemo
tility but may also be associated with reduced lipid peroxidation and dynamic stability and reduced the release of liver-associated cell adhe
leukocyte infiltration. Additionally, remifentanil has been shown to sion molecules and inflammatory factors, thereby reducing hepatic I/R
decrease lipid peroxidase and neutrophil accumulation in ischemic tis injury and protecting liver function [117]. The intravenous anesthetic
sues [109]. The intestinal epithelium is a key component of the intes propofol compounded with remifentanil contributes to the NO/ET-1
tinal mucosal barrier and may be damaged by apoptosis during balance and inhibits the release of the inflammatory factor IL-6 during
intestinal I/R. Remifentanil pretreatment protects the small intestine hepatectomy in patients with cirrhosis [48].
from intestinal I/R injury by inhibiting apoptosis of intestinal mucosal
epithelial cells, and this protective effect seems to act not through κ 3.2.5. Other organs
receptors but through δ and μ receptors [22]. High expression of p38 I/R injury after renal transplantation is unavoidable. The use of an
MAPK mediates the antioxidant and anti-ERS properties of remifentanil esthetics for preventing perioperative renal injury and improving renal
against small intestinal I/R injury and induces protein disulfide isom function has been poorly studied. Dexmedetomidine, a selective
erase A3 (PDIA3) expression [70]. Numerous experiments have α-adrenergic receptor agonist, is widely used as an adjunct to anesthesia
confirmed that administration of remifentanil during tissue ischemia and analgesia. Many studies in recent years have confirmed that dex
protects the intestine from I/R injury. Based on these findings, the po medetomidine plays an important role in I/R injury, inflammation, and
tential pharmacological mechanisms of remifentanil as an I/R protective sepsis in several organs [118,119]. Erkilic’s team found that remi
agent in the intestine and other organs need to be further investigated. fentanil reduced renal I/R injury, but it was less protective than dex
medetomidine [120]. The combination of remifentanil with the volatile
3.2.4. Liver anesthetic isoflurane also alleviated renal I/R injury and was protective
Hepatectomy is a common clinical procedure for the treatment of of the kidney [80]. The mechanism by which remifentanil is used to
cirrhosis and hepatocellular carcinoma, and hepatectomy requires prevent renal I/R injury remains to be investigated. In the case of H/R,
intraoperative blockage of hepatic vessels to reduce intraoperative remifentanil pretreatment enhanced the cell viability and maturation of
bleeding. However, postoperative hepatic revascularization may cause osteoblasts and stimulated the proliferation of osteoblasts and the
I/R injury to the liver, impairing vascular endothelial function and liver expression of related proteins (BMP-2, osteocalcin, AKT, type I collagen,
function and affecting the regenerative capacity of the liver after surgery HIF-1α, etc.), suggesting that remifentanil may attenuate I/R injury
[110,111]. The protective effect of remifentanil on hepatic I/R may be during bone healing [121].
achieved by suppressing the inflammatory response. Yang et al. found Prevention of spinal cord I/R injury during thoracoabdominal aortic
that remifentanil reduced the inflammatory response in hepatic I/R by surgery is a clinical challenge. Opioids are widely used in anesthetic or
analgesic regimens for thoracoabdominal aortic surgery. Nevertheless, it hemodynamic stability is difficult to maintain, the selection of the
has been reported that intrathecal opioid injection may aggravate appropriate anesthetic drug is important to reduce anesthetic compli
neurological injury after spinal cord ischemia [122]. Shirasawa et al. cations and mitigate organ injury. Clamping vital vessels or establishing
reported that neither 0.5 MAC isoflurane compounded with fentanyl nor extracorporeal circulation to temporarily interrupt blood flow is an
remifentanil aggravated spinal cord I/R injury compared with 1 MAC essential step in many surgeries. With revascularization, the corre
isoflurane. Thus, clinically relevant fentanyl or remifentanil does not sponding organ tissue damage or dysfunction is challenging for many
appear to aggravate spinal cord I/R injury in rabbits [123]. Whether surgeons and patients. Many researchers have begun to explore the ef
opioids have a protective effect on spinal cord I/R injury has not been fects of remifentanil on I/R injury in various organs in the clinical
reported. Uterine I/R injury resulted in significant epidermal cell dam setting. Remifentanil is effective in preventing not only organ injury and
age and leukocyte aggregation in rat uterine tissue. Remifentanil in patient mortality but also distant organ damage caused by ischemia [86,
hibits uterine I/R injury by inhibiting oxidative stress and increasing 107,127]. Remifentanil appears to reduce the release of markers of
antioxidant enzymes [57]. myocardial injury after coronary artery bypass grafting [86]. However,
I/R injury is not limited to ischemic tissues since other distant organs another study found that in patients undergoing nonextracorporeal
are also affected by some mediators and toxic products, such as oxygen circulation coronary artery bypass grafting, intravenous anesthesia with
free radicals, prostaglandins, cytokines, and thromboxane, in the body’s propofol combined with remifentanil did not reduce postoperative
circulation [36,124,125]. One of these distant organs is the lung. adverse cardiovascular events compared with inhalation anesthesia
However, Kanbak et al. found that remifentanil did not prevent lung [18]. This may be due to differences in the study metrics and drug
injury due to renal I/R and that its combination with propofol inhibited combination application in the human systemic state. Therefore, the
the antioxidant effect of propofol [126]. This finding seems to be con potential protective effect of remifentanil on organ I/R injury, in addi
trary to the view that the protective effect of remifentanil on organ I/R tion to its analgesic effect, would further broaden its application in the
injury may be due to the increased oxidative damage of erythrocytes by perioperative period. The process of translation from animal studies to
remifentanil and the different mechanisms of action of different drugs. clinical studies is remarkably long, and more clinical studies are needed
We summarize the potential protective effects of remifentanil on other to explore the role of remifentanil in organ I/R injury.
vital organ I/R and the possible mechanisms in Table 2. In addition, remifentanil, as an effective OPR agonist, has gained
particular recognition for its clinical effectiveness in the perioperative
4. Application prospects of remifentanil in clinical I/R injury period because of its rapid onset of action and metabolism. Through this
review, we found that the use of remifentanil before or after organ
In summary, the majority of studies have found that the application ischemia or reperfusion can effectively prevent or attenuate tissue
of remifentanil before ischemia or after reperfusion is generally effective damage or dysfunction caused by I/R. Remifentanil can activate OPRs,
in reducing I/R injury in vital organs. For many procedures in which inhibit calcium overload and apoptosis, attenuate the inflammatory
Table 2
Effects of remifentanil on ischemia-reperfusion injury of other organs.
Organs Experimental models/ Administration dose Function Related pathways or genes Refs
cell types
Renal Rat 2 μg/kg/min, i.v. Protecting ↓ NGAL [120]

Rat 2 μg/kg/min, in vivo Protecting with isoflurane Anti- apoptotic [80]
Brain Rat 1.2 μg/min/kg, i.v. Protecting ↑ CD8+; [64]
↓ CD4+, Cyt-c, caspase-3, caspase-9, JNK, TNF-α,
TNFR1
Rat 5 mg/kg/min, femoral vein Protecting ↑ δ-OPR; [21]
↓ TNF-α, ERK 1/2
Rat 0.6 μg/kg/min, i.v. Protecting ↑ Bcl-2 [106]
↓ Bax
Liver Mice; 30 μg/kg, i.p.； Protecting ↑ HIF-1α, ZEB1; [77]
NCTC 1469 1 μg/ml, in vitro ↓ LIF
Rat 2 mg/kg/min, i.v. Protecting ↑ TNF-α; [79]
↓ NF-κB, p65
Rat; 1 μg/kg bolus; Protecting ↑ NO, iNOs [47]
Hepatocytes 0.2, 2, 20 μg/kg/min, 15 min,
tail vein；
0.1, 1, 10, 100 ng/ml, in vitro
Mice 10 ng/ml, i.p. Protecting ↑ β-arrestin 2; [44]
↓ TLR4
Rat 0.4, 2, 10 μg/kg/min, i.v. Protecting ↑ IL-18BP, IL-1β; [115]
↓ IL-18, TNF-α, IF-γ
Rat 2 μg/ kg/min, i.v. Protecting NM [116]
Intestine Mice 1 μg/kg, tail vein Protecting ↓ IL-6 [81]
Rat; 0.2 μg/kg/min, femoral vein; Protecting ↑ δ-OPRs, μ-OPRs; [22]
IEC-6 cell 0.1, 1, 10, 100 ng/ml, in vitro ↓ caspase-3
Mice 1 μg/ml, 10 ml/kg, i.p. Protecting ↑ PDIA3; [70]
↓ CHOP, Bip, cleaved caspase-3
Rat 2 μg/kg/min, 60 min, tail vein Protecting NM [109]
Bone Human osteoblast cell 0.1, 1 ng/ml, in vitro Protecting ↑BMP-2, osteocalcin, AKT, type I collagen, osterix, [121]
hFOB 1.19 TGF-β1, HIF-1α, RUNX2
Lung Rat 20 μg/kg/min, i.v. Inhibiting the protective effect NM [126]
of propofol
Spinal Rabbit 1 μg/kg/min, ear vein Protecting NM [123]
cord
Uterus Rat 2 μg/kg/min, tail vein Protecting Anti-oxidation [57]
NM, Not mentioned; i.v., intravenously inject; i.p., intraperitoneally inject
response and oxidative stress, and modulate the occurrence of I/R injury Science Foundation of China (92249303 and 81502063).
through multiple mechanisms. Remifentanil will continue to be devel
oped not only as an analgesic but also as a preconditioning agent for References
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Biomedicine & Pharmacotherapy 167 (2023) 115472

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