Activating mu-opioid receptors in the spinal cord mediates the cardioprotective effect of remote preconditioning of trauma

Mei, Bin; Li, Wanhong; Cheng, Xinqi; Liu, Xuesheng; Gu, Erwei; Zhang, Ye

doi:10.5603/cj.a2016.0062

Cited by 8 publications

(6 citation statements)

References 27 publications

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“…This is likely due to multiple differences including genetic and physiological homogeneity of the models, which is not a feature of human populations, physiological differences between humans and model species, human medications, and the exact timing and circumstances of MI (including the timing and location and extent of coronary occlusion). However, the basic finding that RPCT can elicit cardioprotection has been confirmed in four species to date (10,23,24,30,40), and the highly conserved neuroanatomy support that attempts should be made to translate NIC to the clinic.…”

Section: Discussionmentioning

confidence: 98%

Cardioprotection via the skin: nociceptor-induced conditioning against cardiac MI in the NIC of time

Ren

Roessler

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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Timely reperfusion is still the most effective approach to limit infarct size in humans. Yet, despite advances in care and reduction in door-to-balloon times, nearly 25% of patients develop heart failure postmyocardial infarction, with its attendant morbidity and mortality. We previously showed that cardioprotection results from a skin incision through the umbilicus in a murine model of myocardial infarction. In the present study, we show that an electrical stimulus or topical capsaicin applied to the skin in the same region induces significantly reduced infarct size in a murine model. We define this class of phenomena as nociceptor-induced conditioning (NIC) based on the peripheral nerve mechanism of initiation. We show that NIC is effective both as a preconditioning and postconditioning remote stimulus, reducing infarct size by 86% and 80%, respectively. NIC is induced via activation of skin C-fiber nerves. Interestingly, the skin region that activates NIC is limited to the anterior of the T9−T10 vertebral region of the abdomen. Cardioprotection after NIC requires the integrity of the spinal cord from the region of stimulation to the thoracic vertebral region of the origin of the cardiac nerves but does not require that the cord be intact in the cervical region. Thus, we show that NIC is a reflex and not a central nervous system-mediated effect. The mechanism involves bradykinin 2 receptor activity and activation of PKC, specifically, PKC-α. The similarity of the neuroanatomy and conservation of the effectors of cardioprotection supports that NIC may be translatable to humans as a nontraumatic and practical adjunct therapy against ischemic disease. NEW & NOTEWORTHY This study shows that an electrical stimulus to skin sensory nerves elicits a very powerful cardioprotection against myocardial infarction. This stimulus works by a neurogenic mechanism similar to that previously elucidated for remote cardioprotection of trauma. Nociceptor-induced conditioning is equally potent when applied before ischemia or at reperfusion and has great potential clinically.

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Section: Discussionmentioning

confidence: 98%

Cardioprotection via the skin: nociceptor-induced conditioning against cardiac MI in the NIC of time

Ren

Roessler

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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“…Various studies have documented the functional and physical interaction between adenosine and opioid receptors. Indeed, there is a cross-talk between these receptors in inducing cardioprotective effects [ 50 51 52 ]. It has been documented that adenosine may activate opioid receptors to induce cardioprotection during preconditioning [ 22 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…A recent study has also shown an inter-relationship between opioids and adenosine in remote preconditioning-induced cardioprotection. In this study, remote preconditioning of trauma was shown to increase the release of adenosine in the spinal cord and administration of mu-opioid receptor antagonist abolished these effects [ 52 ].…”

Section: Mechanisms Involved In Adenosine Preconditioningmentioning

confidence: 99%

“…Furthermore, PKC inhibitor (chelerythrine) significantly prevented adenosine-induced increase in PKCε-positive mitochondria [ 60 ]. Recently, it has been reported that there is an increase in the levels of adenosine in the spinal cord along with activation of PKCε during remote preconditioning again suggesting the inter-relationship between adenosine and PKCε [ 52 ].…”

Section: Mechanisms Involved In Adenosine Preconditioningmentioning

confidence: 99%

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Mechanisms involved in adenosine pharmacological preconditioning-induced cardioprotection

Singh

Kulshrestha²,

Singh

et al. 2018

Korean J Physiol Pharmacol

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Adenosine is a naturally occurring breakdown product of adenosine triphosphate and plays an important role in different physiological and pathological conditions. Adenosine also serves as an important trigger in ischemic and remote preconditioning and its release may impart cardioprotection. Exogenous administration of adenosine in the form of adenosine preconditioning may also protect heart from ischemia-reperfusion injury. Endogenous release of adenosine during ischemic/remote preconditioning or exogenous adenosine during pharmacological preconditioning activates adenosine receptors to activate plethora of mechanisms, which either independently or in association with one another may confer cardioprotection during ischemia-reperfusion injury. These mechanisms include activation of KATP channels, an increase in the levels of antioxidant enzymes, functional interaction with opioid receptors; increase in nitric oxide production; decrease in inflammation; activation of transient receptor potential vanilloid (TRPV) channels; activation of kinases such as protein kinase B (Akt), protein kinase C, tyrosine kinase, mitogen activated protein (MAP) kinases such as ERK 1/2, p38 MAP kinases and MAP kinase kinase (MEK 1) MMP. The present review discusses the role and mechanisms involved in adenosine preconditioning-induced cardioprotection.

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“…of neurons in the intermediolateral nucleus of the spinal cord and the rostral ventrolateral medulla of the brainstem via the sympathetic pathway (12). The spinal cord has been implicated in the pathogenesis of cardiac injury caused by I/R (4,(13)(14)(15)(16). Furthermore, there is convincing evidence that the heart receives dense innervation from sensory afferent fibers, which peripherally release a variety of vasodilator neuropeptides, such as calcitonin gene-related peptide (CGRP) (17) and substance P (SP), in response to local stimuli (18).…”

Section: Identification Of Lncrna and Mrna Expression Profiles In Ratmentioning

confidence: 99%

Identification of lncRNA and mRNA expression profiles in rat spinal cords at various time‑points following cardiac ischemia/reperfusion

Wang

et al. 2019

Int J Mol Med

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The identification of the expression patterns of long non-coding RNAs (lncRNAs) and mRNAs in the spinal cord under normal and cardiac ischemia/reperfusion (I/R) conditions is essential for understanding the genetic mechanisms underlying the pathogenesis of cardiac I/R injury. The present study used high-throughput RNA sequencing to investigate differential gene and lncRNA expression patterns in the spinal cords of rats during I/R-induced cardiac injury. Male Sprague Dawley rats were assigned to the following groups: i) Control; ii) 2 h (2 h post-reperfusion); and iii) 0.5 h (0.5 h post-reperfusion). Further mRNA/lncRNA microarray analysis revealed that the expression profiles of lncRNA and mRNA in the spinal cords differed markedly between the control and 2 h groups, and in total 7,980 differentially expressed (>2-fold) lncRNAs (234 upregulated, 7,746 downregulated) and 3,428 mRNAs (767 upregulated, 2,661 downregulated) were identified. Reverse transcription-quantitative polymerase chain reaction analysis was performed to determine the expression patterns of several lncRNAs. The results indicated that the expression levels of lncRNA NONRATT025386 were significantly upregulated in the 2 and 0.5 h groups when compared with those in the control group, whereas the expression levels of NONRATT016113, NONRATT018298 and NONRATT018300 were elevated in the 2 h group compared with those in the control group; however, there was no statistically significant difference between the 0.5 h and control groups. Furthermore, the expression of lncRNA NONRATT002188 was significantly downregulated in the 0.5 and 2 h groups when compared with the control group. The present study determined the expression pattern of lncRNAs and mRNAs in rat spinal cords during cardiac I/R. It was suggested that lncRNAs and mRNAs from spinal cords may be novel therapeutic targets for the treatment of I/R-induced cardiac injury.

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Activating mu-opioid receptors in the spinal cord mediates the cardioprotective effect of remote preconditioning of trauma

Abstract: (Cardiol J 2017; 24, 3: 314-323)

Cited by 8 publications

References 27 publications

Cardioprotection via the skin: nociceptor-induced conditioning against cardiac MI in the NIC of time

Cardioprotection via the skin: nociceptor-induced conditioning against cardiac MI in the NIC of time

Mechanisms involved in adenosine pharmacological preconditioning-induced cardioprotection

Identification of lncRNA and mRNA expression profiles in rat spinal cords at various time‑points following cardiac ischemia/reperfusion

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