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.

Figure 1

Diagram summarizing the temporal characteristics of pre- and post-conditioning stimuli (direct and remote), opioid receptor involvement, effects on myocardial I–R outcomes and the potential influences of common co-morbidities. References: 1, Schultz et al., ; 2, Schultz et al., ; 3, Wang et al., ; 4, Weinbrenner et al., ; 5, Zhang et al., ; 6, Wang et al., ; 7, Jang et al., ; 8, Zatta et al., ; 9, Peart et al., ; 10, Gross et al., ; 11, Wong & Lee, ; 12, Peart & Gross, ; 13, Peart & Gross, .

Figure 2

Intracellular signal paths coupled to the opioid receptors and implicated in cardiac stress signalling and cardioprotection. Receptor agonism leads to activation of PI3K/Akt and RISK pathway components (including PKs A, B, C and G), MAPKs (ERK, p38), ROS generation, JAK-STAT signalling, phospho-regulation of effector molecules such as GSK3β and connexin-43, and activation of mitochondrial K_ATP and K_Ca channels. These paths may converge on inhibition of the mPTP to preserve mitochondrial integrity and function. Not shown opioid receptor-coupled signal paths also affect expression/translocation of pro- and anti-apoptotic proteins, including Bax and Bcl-2, and opioid receptors may additionally participate in activation of the cardioprotective survivor activating factor enhancement (SAFE) pathway (involving TNF-α-dependent activation of STAT3 signalling).