Opioid receptors and cardioprotection – ‘opioidergic conditioning’ of the heart

Abstract

Ischaemic heart disease (IHD) remains a major cause of morbidity/mortality globally, firmly established in Westernized or 'developed' countries and rising in prevalence in developing nations. Thus, cardioprotective therapies to limit myocardial damage with associated ischaemia-reperfusion (I-R), during infarction or surgical ischaemia, is a very important, although still elusive, clinical goal. The opioid receptor system, encompassing the δ (vas deferens), κ (ketocyclazocine) and μ (morphine) opioid receptors and their endogenous opioid ligands (endorphins, dynorphins, enkephalins), appears as a logical candidate for such exploitation. This regulatory system may orchestrate organism and organ responses to stress, induces mammalian hibernation and associated metabolic protection, triggers powerful adaptive stress resistance in response to ischaemia/hypoxia (preconditioning), and mediates cardiac benefit stemming from physical activity. In addition to direct myocardial actions, central opioid receptor signalling may also enhance the ability of the heart to withstand I-R injury. The δ-and κ-opioid receptors are strongly implicated in cardioprotection across models and species (including anti-infarct and anti-arrhythmic actions), with mixed evidence for μ opioid receptor-dependent protection in animal and human tissues. A small number of clinical trials have provided evidence of cardiac benefit from morphine or remifentanil in cardiopulmonary bypass or coronary angioplasty patients, although further trials of subtype-specific opioid receptor agonists are needed. The precise roles and utility of this GPCR family in healthy and diseased human myocardium, and in mediating central and peripheral survival responses, warrant further investigation, as do the putative negative influences of ageing, IHD co-morbidities, and relevant drugs on opioid receptor signalling and protective responses.

Effect and Safety of Morphine Use in Acute Anterior ST‐Segment Elevation Myocardial Infarction

“…In experimental models of ischemia reperfusion injury, morphine inhibits the mitochondrial permeability transition pore24 opening through μ and κ myocardial opioid receptors,25, 26 and induced a significant cardioprotective effect 27. Morphine also stimulates the reperfusion injury salvage kinase pathway 24.…”

“…Morphine also stimulates the reperfusion injury salvage kinase pathway 24. In animal studies, these mechanisms have been associated with a reduction of infarct size following intravenous or intrathecal morphine use before or immediately after reperfusion 28, 29, 30.…”

One-year outcome of the sevoflurane in acute myocardial infarction randomized trial

“…Opioids have been reported to provide cardioprotection, and therefore, the use of fentanyl may have masked a potential protective effect of sevoflurane. 29 It is also possible that the protective effect of sevoflurane seen in animal models and in some of the human studies does not apply to patients presenting with MI. Such an effect may also be reduced in patients with diabetes.…”

Anesthetic-induced myocardial protection in cardiac surgery: relevant mechanisms and clinical translation

“…Indeed, experimental data have demonstrated negative changes in opioid receptor responses related to pre-and post-conditioning with age and the aforementioned comorbidities [26].…”