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Abstract

Remote ischemic preconditioning (RIPC) is an intriguing process whereby transient regional ischemia and reperfusion episodes to remote tissues including skeletal, renal, mesenteric provide protection to the heart against sustained ischemia–reperfusion-induced injury. Clinically, this technique has been used in patients undergoing various surgical interventions including coronary artery bypass graft surgery, abdominal aortic aneurysm repair, percutaneous coronary intervention, and heart valve surgery. The endogenous opioid system is extensively expressed in the brain to modulate pain sensation. Besides the role of opioids in relieving pain, numerous researchers have found their critical involvement in evoking cardioprotective effects. Endogenous opioids including endorphins, enkephalins, and dynorphins are released during RIPC and are critically involved in mediating RIPC-induced cardioprotective effects. It has been suggested that during RIPC, the endogenous opioids may be released into the systemic circulation and may travel via bloodstream that act on the myocardial opioid receptors to induce cardioprotection. The present review describes the potential role of opioids in mediating RIPC-induced cardioprotection.

Keywords

opioids cardioprotection remote ischemic preconditioning humoral

Introduction

Remote ischemic preconditioning (RIPC) is a therapeutic treatment strategy whereby alternate cycles of preconditioning ischemia and reperfusion are delivered to a remote organ (other than heart) to confer protection in the target organ, that is, heart, against sustained ischemia–reperfusion-induced injury.^1,2 Clinically, RIPC technique has been used to alleviate myocardial injury in patients undergoing various surgical interventions including coronary artery bypass graft surgery, abdominal aortic aneurysm repair, percutaneous coronary intervention, and heart valve surgery.^1,3 According to the neurogenic theory of RIPC, short ischemic episodes release the endogenous mediators, which stimulate the afferent nerve fibers and consequently relay signals to the efferent nerve fibers terminating at the heart to provide cardioprotection.⁴ On the other hand, according to the humoral theory of RIPC, the endogenous substances are released into the bloodstream and reach the heart to exert cardioprotective effects.^4,5

Endogenous opioid peptides are widely distributed in the central nervous system (CNS) and peripheral nervous system and act as neuromodulators and neurotransmitters to regulate a variety of processes including cardiovascular homeostasis and cardiac tolerance against sustained ischemia–reperfusion-induced injury.^6
-8 Endogenous opioids are classified into enkephalins, endorphins, and dynorphins and bind to mu (μ), delta (δ), kappa (κ) opioid receptors, respectively. Besides the well-recognized role of opioids in managing chronic pain,⁹ opioids have been used to reduce acute hemorrhagic shock-induced myocardial injury.¹⁰ Endogenous opioids act in autocrine/paracrine/endocrine fashion to modulate the functioning of the heart.¹¹ Furthermore, the heart itself is also a potential source of opioid production as opioid receptor mu subunit gene (OPRM1), opioid receptor kappa subunit gene (OPRK1), and opioid receptor delta subunit gene (OPRD1) are localized in the heart.¹¹ In addition, opioid receptors are essentially involved in mediating preconditioning-induced cardioprotective effects.¹² There have been cumulating evidence indicating the involvement of endogenous opioids in mediating RIPC-induced cardioprotection.^13

-17 Therefore, the present review describes the role of opioids in mediating RIPC-induced cardioprotection.

Clinical Implications and Factors Affecting the Outcome of RIPC

Remote ischemic preconditioning is an endogenous cardioprotective phenomenon that has been translated into clinical setups.¹⁸ Clinically, RIPC stimulus is delivered via alternate inflation (≥20 mm above the systolic blood pressure) and deflation of the blood pressure cuff tied on the upper arm of the individual. Three to 4 consecutive cycles in the form of transient limb ischemia serve as a noninvasive, safe, and feasible technique to provide protection against sustained ischemia–reperfusion injury. Furthermore, skeletal muscles have relatively more resistance against ischemia–reperfusion injury¹⁹ in comparison to other organs including kidney and intestine. Remote ischemic preconditioning has shown to reduce the myocardial injury in patients undergoing coronary artery bypass grafting.^18,20 Furthermore, in patients who underwent elective percutaneous coronary interventions, RIPC led to a reduction in major adverse cardiac and cerebral events even after 6 years.²¹ In addition, RIPC has the potential to alleviate kidney injury in patients undergoing cardiac surgeries,²² coronary artery angiography, and renal transplantation.²³ Remote ischemic preconditioning also improved cognitive performance in patients undergoing cardiac surgeries.²⁴ Remote ischemic preconditioning and concomitant remote ischemic postconditioning stimulus in the patients undergoing cardiac surgery with cardiopulmonary bypass led to pulmonary protective effects.²⁵ Apart from this, the application of RIPC in the healthy individuals for 7 consecutive days significantly improved the endothelial function and microcirculation.²⁶

There are various factors that affect the beneficial effects of RIPC in humans including aging, comorbidities, and concurrent medication. Aging is an important factor that significantly affects RIPC-induced cardioprotective effects. Animal studies reveal that increasing age reduces the preconditioning-induced cardioprotective effects and makes the senescent myocardium more vulnerable to ischemia–reperfusion injury.^27,28 Clinically, preconditioning-induced cardioprotective effects are lost in the aged individuals.²⁹ The possible reason may be that aging reduces the contractile function and weakens cardioprotective mechanisms.³⁰ Furthermore, antecedent angina prior to myocardial infarction is equivalent to ischemic preconditioning and offers cardioprotective effects in adult patients but is lost in aged individuals.^31
-33 However, Moro et al reported a greater increase in flow-mediated dilation (FMD) in elderly individuals (181%) in comparison to young (69%) in response to RIPC stimulus. Although the percentage increase was higher in elderly persons, the absolute FMD in young individuals (20.6) was significantly higher as compared to FMD in elderly persons (14.2).³⁴ The effectiveness of RIPC is significantly influenced by comorbidities including stable angina and type II diabetes. The patients with stable angina pectoris experience transient ischemia and have a natural preconditioning effect on the heart, and patients with angina have a better prognosis in myocardial infarction.^31,32 Accordingly, the patients with stable angina may not gain additional benefit from RIPC. Similar to stable angina, peripheral arterial disease also produces natural preconditioning effect, and accordingly, the patients with this disease do not gain additional benefit from remote preconditioning. In patients with diabetes, the cardioprotection offered by preconditioning is reduced, probably due to the accumulation of glycosylated proteins, which may suppress the mitochondrial function including mitochondrial permeability transition pore (mPTP) formation.³⁵ The concurrent medication also significantly influences the effect of RIPC including sulfonylureas (oral hypoglycemic agents), which may inhibit the mitochondrial ATP-sensitive potassium channel (K_ATP) channels and attenuate RIPC-induced cardioprotection.^36,37 The type of anesthesia used during surgery may also influence the outcome of RIPC. The use of propofol and isoflurane does not confer additional benefit, possibly due to the ability of the anesthetics to mitigate the ischemic response in humans, required to produce the preconditioned state.^38,39

Role of Opioids in RIPC

Endogenous opioids including endorphins, enkephalins, and dynorphins are released into the bloodstream in response to remote stimulus and are critically involved in mediating RIPC-induced cardioprotective effects.^13

-17 Metabolic stressors including ischemia may evoke the release of endogenous opioids from the peripheral tissues to provide protection against sustained ischemia–reperfusion injury in the heart.^40

-43 Patel et al described the putative role of opioids in mediating RIPC-induced cardioprotection in an intact rat model of myocardial infarction. Mesenteric remote preconditioning (15-minute occlusion followed by 10-minute reperfusion)-induced cardioprotective effects were completely abolished in the presence of naloxone (nonspecific opioid antagonist), suggesting that the endogenous release of opioids may mediate mesenteric remote preconditioning-induced cardioprotection.¹³ Additionally, in isolated adult rabbit cardiomyocytes, morphine provided protection against simulated ischemia (180 minute) that was nearly equivalent to that of preconditioning (15-minute simulated ischemia followed by 15-minute reperfusion). Moreover, preconditioning-induced protective effect was completely abolished in the presence of naloxone,⁷ emphasizing the role of opioids in cardioprotection.

Shimizu and coworkers also reported that remote hind limb preconditioning (4 alternate cycles of 5-minute ischemia and reperfusion) induces cardioprotection in rabbits against regional myocardial ischemia, that is, 30-minute occlusion of the left anterior descending coronary artery and 120-minute reperfusion. Pretreatment with rabbit RIPC-plasma and RIPC-dialysate (acquired using 15-kDa cutoff dialysis membrane) protected naive donor Langendorff-perfused rabbit hearts against myocardial necrosis. This suggests that the transient limb ischemic episode induces the release of factors with molecular mass <15 kDa into the bloodstream. This contention was further supported by more observations whereby the subjection of RIPC-human dialysate to Langendorff-perfused rabbit hearts remarkably reduced ischemia–reperfusion-induced cardiac necrosis. In addition, human and rabbit RIPC dialysate also produced protective effects in isolated fresh cardiomyocytes. However, the effectiveness of rabbit RIPC dialysate was significantly reduced on passing through a C₁₈ hydrophobic column. Interestingly, the eluate retained the capability of inducing same level of cardioprotection. Thus, the authors hypothesized that opioids are endogenous molecules with size <15 kDa (500-800 Da) and may be putative mediators of RIPC. The authors verified the hypothesis by demonstrating the attenuation of cardioprotective effect of RIPC-plasma and RIPC-dialysate in the presence of naloxone. Therefore, the authors proposed that RIPC induces release of low-molecular-weight (<15 kDa), hydrophobic-circulating factors, probably opioids, to elicit cardioprotective effects.¹⁶ Later on, Michelsen et al reported that the delivery of dialysates (after human RIPC) to isolated rabbit hearts reduced infarct size that was abolished in the presence of naloxone.⁴⁴ Surendra et al further supported these findings by demonstrating that the plasma dialysate (derived from remotely preconditioned rabbits) induces cardioprotection in freshly isolated cardiomyocytes via the activation of opioid receptors.⁴⁵ Furthermore, it has been reported that morphine reduces the threshold of RIPC and substantiates the cardioprotective effects of RIPC in rats.^46

-50 Pretreatment with morphine and 1 cycle of femoral artery ischemia interspersed with 5-minute reperfusion-induced cardioprotection was equivalent to 3 cycles of cardioprotection due to femoral RIPC. However, the combination of subthreshold dose of morphine and 1 cycle of RIPC-induced cardioprotection was remarkably abolished in the presence of naloxone.⁴⁶ Thus, this indicates that 3 cycles of femoral RIPC result in cumulative increase in opioids levels, whereas 1 cycle of femoral RIPC does not sufficiently increase the opioid levels and is therefore compensated by subthreshold dose of morphine to provide cardioprotection.

Although the preclinical studies have shown the crucial involvement of opioid signaling in mediating remote preconditioning-dependent cardioprotective effects, there has been a clinical study negating the role of opioidergic system activation in inducing cardioprotective effects.⁵¹ Clinically, the remote limb preconditioning (3 cycles of the upper limb cuff inflation–deflation) was shown to produce myocardial protection in patients undergoing coronary artery bypass grafting with cold crystalloid cardioplegia in terms of serum troponin I and nitric oxide synthase (NOS) levels. However, the administration of tramadol before undergoing coronary artery bypass grafting with cold crystalloid cardioplegia did not significantly reduce myocardial injury.⁵¹ Tramadol elicits protective effects against myocardial ischemia–reperfusion injury,^52,53 possibly via activating opioidergic, serotonergic receptors, increasing NO release, and enhancing noradrenaline reuptake.⁵² Perhaps, the dose of tramadol used in the study was quite large and led to serotonin syndrome in 2 patients. Indeed, serotonin exhibits differential effects in normal and damaged human coronary arteries. In normal human coronary arteries, serotonin has a vasodilatory effect; however, in diseased coronary arteries (ruptured endothelium), serotonin exhibits vasoconstricting effect.⁵⁴ Accordingly, tramadol-induced vasoconstriction during bypass grafting may be responsible for its nonsignificant cardioprotective effects (Table 1).

Table 1.

Preclinical Evidence for Remote Ischemic Preconditioning (RIPC)-Induced Opioids Release in Alleviating Ischemia–Reperfusion-Induced Myocardial Injury.

S. No.	Experimental Protocol	Pharmacological Modulators/Techniques/Transgenic Animals	Comments
1	15-minute simulated ischemia followed by 15-minute reperfusion prior to 180-minute sustained ischemia isolated adult rabbit cardiomyocytes	Naloxone	RIPC-induced cardioprotective effects were completely abolished in the presence of naloxone indicating the role of opioids in cardioprotection⁷
2	Single cycle of 15-minute occlusion followed by 10-minute reperfusion prior to sustained 30-minute occlusion–120-minute reperfusion of coronary artery in intact rat model of myocardial infarction	Naloxone	RIPC-induced cardioprotective effects were completely abolished in the presence of naloxone indicating the role of opioids in cardioprotection¹³
3	4 alternate cycles of 5-minute ischemia and reperfusion of the hind limb prior to 30-minute occlusion of the left anterior descending coronary artery and 120-minute reperfusion Pretreatment-naive donor Langendorff perfused rabbit hearts with rabbit RIPC-plasma and RIPC-dialysate (acquired using 15-kDa cutoff dialysis membrane) Subjection of isolated fresh cardiomyocytes to human and rabbit RIPC dialysate	C₁₈ hydrophobic column	RIPC-plasma and RIPC dialysate-protected naive donor rabbit hearts from ischemia–reperfusion-induced cardiac necrosis Human and rabbit RIPC dialysate also produced protective effects in isolated fresh cardiomyocytes¹⁶
4	Subjection of RIPC dialysate obtained after 4 alternate cycles of 5-minute ischemia and reperfusion of the hind limb to freshly isolated cardiomyocytes	Naltrindole; 5′-guanidinonaltrindole	Specific blockade of δ and κ receptors with naltrindole and 5′-guanidinonaltrindole abolished RIPC dialysate-induced cardioprotection⁴⁵
5	3 cycles of femoral RIPC Subthreshold dose of morphine and 1 cycle of RIPC prior to 30-minute ischemia by the left coronary artery occlusion–120-minute reperfusion	Naloxone	3 cycles of femoral RIPC and subthreshold dose of morphine and 1 cycle of RIPC resulted in cardioprotection that was abolished in the presence of naloxone⁴⁶
6	15-minute occlusion and reperfusion of the infrarenal aorta prior to 30-minute regional ischemia–30-minute reperfusion	BNTX	RIPC-induced cardioprotection is mediated via activation of δ₁-opioid receptors¹⁴
7	3 alternate cycles of 10-minute ischemia and reperfusion to the hind limb prior to 4-hour ischemia–48-hour reperfusion	Naloxone; BNTX	RIPC reduced infarction in latissimus dorsi, gracilis, and rectus abdominis muscle flaps⁵⁵
8	3 alternate cycles of 5-minute occlusion reperfusion of the right femoral artery prior to 30-minute occlusion–120-minute reperfusion of the left anterior descending coronary artery for	50 488 H; norbinaltorphimine; atractyloside	50 488 H, RIPC-induced cardioprotection that was abolished in the presence of norbinaltorphimine, atractyloside indicating involvement of receptors and inhibition of mPTP formation¹⁵
9	3 alternate cycles of 5-minute ischemia and reperfusion Remote preconditioning of trauma (stimulation of cutaneous pain fibers 15 minutes) before 30-minute ischemia–120-minute reperfusion	Naloxone methiodide; hexamethonium; naltrindole; D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂ (CTOP)	RIPC-induced cardioprotection was abolished in the presence of naloxone methiodide (intrathecal), hexamethonium, CTOP indicating that spinal µ-opioid receptors are involved in neurogenic signaling of RIPC/remote preconditioning of trauma to induce cardioprotection¹⁷

Abbreviations: mPTP, mitochondrial permeability transition pore; RIPC, remote ischemic preconditioning stimulus.

It may be manifested that during RIPC, endogenous opioids may be released into the systemic circulation that may confer cardioprotective effects during sustained ischemia–reperfusion injury.

Involvement of Subtypes of Opioid Receptors in RIPC

Among the subtypes of opioid receptors, the studies have shown the key role of μ,¹⁷ κ,¹⁵ and δ⁵⁵ opioid receptors in RIPC-induced cardioprotection. The scientists have mainly used specific and nonspecific pharmacological agents to delineate the role of specific subtypes of opioid receptors.^14,45,55

Role of δ-opioid receptor activation in RIPC

Weinbrenner et al documented that infrarenal preconditioning (occlusion and reperfusion of the aorta)-induced cardioprotective effects were significantly abolished in the presence of 7-Benzylidenenaltrexone (BNTX) (δ₁-opioid receptor antagonist), suggesting that RIPC-induced cardioprotection is mediated by the activation of δ₁-opioid receptors.¹⁴ This contention is further supported by a study demonstrating the attenuation of remote hind limb preconditioning-induced reduction in infarct size in latissimus dorsi, gracilis, and rectus abdominis muscle flaps in the presence of naloxone and BNTX (δ₁-antagonist).⁵⁵ Accordingly, it may be proposed that the remote hind limb preconditioning possibly stimulates the release of enkephalins into the circulation (humoral pathway) to protect the distant skeletal muscles from sustained ischemia–reperfusion injury via the activation of δ₁-opioid receptors.

Role of κ-opioid receptor activation in RIPC

A study by Zhang et al demonstrated the role of κ-opioid receptors in mediating RIPC-induced cardioprotection. The remote hind limb preconditioning and exogenous administration of U-50 488 H (κ-opioid agonist) was shown to produce comparable cardioprotective effects. However, the cardioprotective effects of both remote hind limb preconditioning and U-50 488 H were significantly abolished in the presence of norbinaltorphimine (nor-BNI; κ-opioid receptor antagonist) and atractyloside (mPTP activator). Furthermore, RIPC significantly increased the plasma dynorphin levels, and exogenous administration of dynorphin itself resulted in cardioprotection.¹⁵ It is well known that long-lasting opening of mPTP in cardiomyocytes may result in mitochondrial dysfunction and myocardial cell necrosis.⁵⁶ Previous study also demonstrated that activation of opioid receptors attenuates myocardial injury by reducing mPTP formation.¹⁵ Thus, the authors proposed that RIPC induces cardioprotection by releasing dynorphin in the circulation, which activates the cardiac κ-opioid receptors to subsequently inhibit mPTP formation. The role of δ and κ-opioid receptors in RIPC was substantiated by Surendra et al who reported that RIPC dialysate, met-enkephalin (δ-opioid receptor agonist) and dynorphin B (κ-opioid receptor agonist) significantly reduced the percentage of dead cardiomyocytes following 45-minute simulated ischemia/60-minute simulated reperfusion. However, the specific blockade of δ-opioid receptors with naltrindole and κ-opioid receptors with 6′-guanidinonaltrindole completely abrogated RIPC dialysate-induced cardioprotection in cardiomyocytes, indicating the involvement of δ- and κ-opioid receptors in mediating cardioprotective effects.⁴⁵ Accordingly, it may be suggested that the remote hind limb preconditioning possibly stimulates the release of dynorphins into the circulation, which induces cardioprotection by the activation of δ₁-opioid receptors and subsequent inhibition of mPTP formation.

Role of µ-opioid receptor activation in RIPC

In contrast to the above studies showing the role of δ- and κ-opioid receptors, a study by Wong et al demonstrated the role of µ-opioid receptors but no role of δ and κ receptors in inducing cardioprotective effects. The authors documented that the remote limb preconditioning (3 alternate cycles of 5-minute ischemia and reperfusion) and remote preconditioning of trauma (stimulation of cutaneous pain fibers 15 minutes before sustained ischemia)-induced myocardial protection were significantly inhibited by intrathecal administration of naloxone methiodide and intravenous (IV) administration of hexamethonium. This suggests that the spinal opioid receptors are involved in neurogenic signaling of RIPC/remote preconditioning of trauma to induce cardioprotection.

Furthermore, the authors have shown that D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂, CTOP (µ-opioid receptor antagonist) but not naltrindole (δ₁-opioid receptor antagonist) and or-BNI (κ-opioid receptor antagonist) attenuated RIPC-induced cardioprotection indicating the involvement of µ-opioid receptors in mediating protection. Thus, the authors postulated that the spinal µ-opioid receptors possibly relay the signals between afferent and efferent pathways to mediate RIPC-induced cardioprotective effects.¹⁷

Discussion

Exogenous and endogenous opioids exhibit pharmacological effects via interacting with G-protein-coupled opioid receptor system, encompassing δ-, κ-, and µ-opioid receptors.^57,58 All the subtypes of opioid receptors are widely distributed in the atria and the ventricles of the heart for initiating a cascade of events involved in cardioprotection against sustained ischemia–reperfusion injury.^59,60 The heart is a complex neuroendocrine organ that synthesizes endogenous opioids in the heart that may act in autocrine or paracrine fashion to modulate functioning of the heart.¹¹

Possible Source of Opioid Release During RIPC

Although the role of opioidergic system in RIPC has been well defined, the possible source of opioids production/release has not been demonstrated. The study by Wever et al demonstrated that the hind limbs may be the potential source of opioid production and release during the remote hind limb preconditioning-induced protection against sustained ischemia–reperfusion injury in the kidney.⁶¹ This contention is further supported by a study demonstrating that the transient ischemic episode potentially evokes the release of enkephalins from the isolated skeletal muscles and the heart itself.⁶² It may be possible that remote regions convey signals to the heart, and it may respond by releasing opioids, which act in autocrine manner to produce cardioprotection from ischemia–reperfusion-induced injury. The heart is a potential source of opioid production as OPRM1, OPRK1, and OPRD1 genes are localized in the heart.^11, ⁶²

Neural Versus Humoral Pathway

The neurogenic theory of RIPC postulates that short ischemic episodes induce the release of endogenous mediators, which stimulate the afferent nerve fibers and consequently relay signals to the efferent nerve fibers terminating at the heart to provide cardioprotection.⁴ Researchers have supported this notion using a ganglionic blocker, hexamethonium, to show that the RIPC-induced endogenous release of opioids activates neurogenic pathway to provide cardioprotective effects.¹⁷ This indicates that RIPC stimulus possibly increases local release of endogenous opioids to stimulate spinal afferent nerve endings to relay signals to the CNS to produce cardioprotective effects.

On the other hand, according to the humoral theory of RIPC, the endogenous substances are released into the bloodstream and reach the heart to exert cardioprotective effects.^4,5 Remote ischemic preconditioning stimulus possibly releases humoral circulating endogenous peptides into the bloodstream that act on the myocardial opioid receptors to induce cardioprotective effects.^13,16 Thus, based on the cumulating evidence, it can be concluded that RIPC stimulus possibly increases the endogenous release of opioids from tissues including skeletal muscles or the heart itself that may act via humoral or neurogenic pathway to activate cardiac opioid receptors to induce cardioprotection (Figure 1).

Figure 1.

Remote ischemic preconditioning stimulus from various organs including kidney, mesentery, and limb results in enhanced release of opioids (endorphins, enkephalins, and dynorphins) into the systemic circulation that reach the heart to activate the respective receptors to produce cardioprotection. Indeed, RIPC stimulus may induce translation of the genes regulating opioid formation to augment the levels of endorphins, enkephalins, and dynorphins. Opioids-triggered signaling cascade in RIPC is unexplored. However, based on preconditioning studies, it may be proposed that enkephalin may result in sequential activation of PI3-K, Akt, extracellular signal-regulated kinase (ERK), nitric oxide synthase (NOS), and mitochondrial K_ATP channels to transiently increase reactive oxygen species (ROS) generation and inhibit mitochondrial permeability transition pore (mPTP) formation during sustained ischemia. Furthermore, endorphins probably activate ERK and subsequently inhibit GSK-3β to increase the generation of mitochondrial heat shock protein 90 and decrease myocardial necrosis. Endorphins simultaneously activate signal transducer and activator of transcription (STAT) 3 to reduce mPTP formation in the cardiomyocytes. Dynorphin release also initiates PI3-K signaling and opens mitochondrial K_ATP channels to induce cardioprotection.

Opioid-Triggered Signaling Cascade in Conditioning of the Heart

The signaling in opioid-dependent cardioprotection during RIPC is less well defined. However, based on the type of opioid receptor, the different signal transduction pathways in mediating opioid-induced cardioprotection during preconditioning and pharmacological conditioning have been demonstrated.^63,64 The δ-receptor activation during pharmacological preconditioning sequentially activates phosphatidylinositol 3-kinase, Akt, extracellular signal-regulated kinase (ERK), NOS, and mitochondrial K_ATP channels to transiently increase reactive oxygen species generation and inhibit mPTP formation during sustained ischemia–reperfusion injury.⁶⁵ Indeed, the role of activation of phosphatidylinositol 3-kinase/Akt⁶⁶, eNOS⁶⁷, ERK_1/2,⁶⁸ and mitochondrial K_ATP channels⁶⁹ has been demonstrated during RIPC. This indicates that during RIPC, the activation of δ-opioid receptors may stimulate phosphatidylinositol 3-kinase, Akt, ERK, NOS, and mitochondrial K_ATP channels to ensue cardioprotection. Meanwhile, the activation of µ-opioid receptors during morphine preconditioning confers cardioprotective effects via activation of ERK^64,70 and subsequent inhibition of glycogen synthase kinase-3β, which increases the generation of mitochondrial heat shock protein 90.⁷¹ Very recently, Dorsch and co-workers reported that morphine preconditioning induces the activation of signal transducer and activator of transcription (STAT) 3 and protein kinase A to reduce mPTP formation in the cardiomyocytes.⁷² The ERK and glycogen synthase kinase 3β are components of reperfusion injury salvage kinase (RISK) pathway but STAT-3 is a part of survivor activating factor enhancement (SAFE) pathway.⁴⁷ Thus, it may be speculated that µ-opioid receptor activation elicits cardioprotection via activation of distinct RISK and SAFE pathways. Therefore, it may be proposed that the activation of µ-opioid receptors during RIPC may stimulate RISK^66,68 and SAFE pathways^73,74 to provide cardioprotection.

Apparently, the activation of κ-opioid receptors attenuates myocardial injury by reducing mPTP formation.¹⁰ Furthermore, Zhang and Wong reported that pharmacological κ-opioid receptor stimulation suppresses cyclic adenosine monophosphate (cAMP) accumulation via the activation of the phosphoinositol/calcium ions pathway in the heart.⁷⁵ This is further substantiated by a study whereby remote microvascular preconditioning reduces cAMP levels to induce tissue protective effects.⁷⁶ Furthermore, the activation of κ receptor during preconditioning stimulates protein kinase C to activate mitochondrial K_ATP channels and enhance the generation of heat shock proteins to provide cardioprotection.⁷⁷ Likewise, κ-opioid receptor-dependent activation of phosphatidylinositol 3-kinase pathway and mitochondrial K_ATP channels has also been suggested in providing cardioprotection.⁷⁸ Thus, it may be proposed that phosphatidylinositol 3-kinase,⁶⁶ PKC activation,⁷⁹ may stimulate mitochondrial K_ATP channels to provide cardioprotection.

Relationship of Opioids With Adenosine and Other Mediators in RIPC

The involvement of other mediators including adenosine,⁸⁰ NO,⁴⁹ and K_ATP channels⁸¹ has been well reported in mediating RIPC-induced cardioprotection. Perhaps, opioids may interact with these mediators to induce cardioprotective effects. Indeed, there have been some studies that have suggested the possible cooperative interactions between adenosine and opioids in transducing the cardioprotective signals in the heart during RIPC.^45,82 Surendra et al demonstrated the existence of functional interaction between opioid and adenosine receptors in mediating RIPC-induced cardioprotective effects in the isolated cardiomyocytes.⁴⁵ The authors have shown that nonselective adenosine receptor blocker (p-sulfophenyl)-theophylline (SPT) and selective adenosine A₁ receptor blocker Dipropylcyclopentylxanthine (DPCPX), but not selective A₃ receptor blocker, abolished RIPC dialysate, met-enkephalin-induced, and dynorphin B-induced cardioprotection, suggesting that met-enkephalin-δ and dynorphin-κ mutually interact with adenosine A₁ receptors to mediate cardioprotective effects.⁴⁵ The functional interaction between adenosine and opioids was further corroborated by a previous study, which indicated that adenosine may be a possible mediator for eliciting opioid preconditioning-induced cardioprotective effects.⁸² Intrathecal morphine-induced cardioprotective effects were significantly inhibited in the presence of IV 8-SPT. However, intrathecal administration of 8-(p-sulfophenyl)-theophylline (8-SPT) before, but not after morphine, abolished the cardioprotective effects of intrathecal morphine. This suggests that both initiation and mediation of intrathecal morphine-induced cardioprotection involve the activation of peripheral adenosine receptors. However, the central adenosine receptors are primarily involved in the initiation of morphine-induced cardioprotection.⁸²

The potential cross talk between adenosine and opioid receptors in the heart has been shown by various groups of researchers.^83
-85 Peart and Gross revealed that adenosine and opioids elicit cardioprotective effects via cross talk between these respective receptors. The authors demonstrated that morphine-induced cardioprotective effects against sustained ischemia–reperfusion in rat model of myocardial infarction were abolished in the presence of selective A₁ receptor blocker, DPCPX.⁸³ Very recently, Lee and coauthors also demonstrated the functional concert between opioid and adenosine receptors during remifentanil preconditioning. The authors showed that remifentanil preconditioning-induced cardioprotection in the isolated rat hearts was blocked in the presence of nonselective adenosine antagonist 8-SPT, A₁ receptor antagonist (DPCPX), and A_2B receptor antagonist (MRS1706). This indicates that there might be an existence of potential cross talk between opioid and adenosine receptors during remifentanil preconditioning, and adenosine A₁ and A_2B receptors are likely involved in mediating the cardioprotective effects of opioids.⁸⁵

Interestingly, in adenosine A₁ receptor agonist, CCPA-induced cardioprotective effects against sustained ischemia–reperfusion in a rat model of myocardial infarction were abolished in the presence of δ₁ receptor antagonist, BNTX. It indicates that the cardioprotective effects of adenosine involve the activation of opioid receptors.⁸³ Furthermore, Sharma et al demonstrated that adenosine preconditioning-induced cardioprotection against sustained ischemia–reperfusion-induced injury in the isolated rat hearts was significantly abolished in the presence of naloxone. Furthermore, the restoration of attenuated cardioprotection of adenosine preconditioning in the isolated diabetic rat hearts, but was restored in the presence of dipyridamole (adenosine reuptake inhibitor), was also abolished in the presence of naloxone. These results emphasize that adenosine preconditioning-induced cardioprotection involves the activation of opioid receptors.⁸⁴ Thus, possible cooperative interactions between adenosine and opioids may take place in transducing the cardioprotective signals in the heart during RIPC.

Future Directions

The possible source of opioid release during RIPC, either the remote organ subjected to preconditioning ischemia or the heart itself, needs to be explored.

The involvement of either neurogenic/humoral pathway or both and their interrelationship needs to be explored.

The signaling cascade involved in mediating preconditioning-induced cardioprotection has been explored. However, the same pathways are also involved in mediating RIPC-induced cardioprotection and need experimental verification.

Conclusion

Remote ischemic preconditioning is a therapeutic treatment strategy that alleviates ischemia–reperfusion-induced injury in the heart. It probably induces the release of endogenous opioids from the tissues including skeletal muscles or the heart itself that may act via humoral or neurogenic pathway to activate cardiac opioid receptors to produce cardioprotection. However, precise studies are required to explore the possible signaling pathway involved in producing RIPC-induced cardioprotective effects.

Footnotes

Acknowledgment

The authors are thankful to Department of Science and Technology F. No. SB/SO/HS/0004/2013, New Delhi, for their gratefulness for providing us financial assistance and Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India, for supporting us.

Author Contributions

Puneet Kaur Randhawa drafted the manuscript, critically revised the manuscript, and agrees to be accountable for all aspects of work ensuring integrity and accuracy. Amteshwar Singh Jaggi contributed to conception, contributed to acquisition, and gave final approval.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Opioids in Remote Ischemic Preconditioning-Induced Cardioprotection

Abstract

Keywords

Introduction

Clinical Implications and Factors Affecting the Outcome of RIPC

Role of Opioids in RIPC

Involvement of Subtypes of Opioid Receptors in RIPC

Role of δ-opioid receptor activation in RIPC

Role of κ-opioid receptor activation in RIPC

Role of µ-opioid receptor activation in RIPC

Discussion

Possible Source of Opioid Release During RIPC

Neural Versus Humoral Pathway

Opioid-Triggered Signaling Cascade in Conditioning of the Heart

Relationship of Opioids With Adenosine and Other Mediators in RIPC

Future Directions

Conclusion

Footnotes

Acknowledgment

Author Contributions

Declaration of Conflicting Interests

Funding

References