Heart opioid receptors

In 1976 Martin proposed the theory that there are three subtypes of opioid receptor on the basis of behavioural studies using a chronic spinal dog model which revealed that the opioids morphine (mu) (1), ketazocine (kappa) (2) and A-allylnormetazocine (SKF 10047) (4) (sigma) had different effects on respiration, heart rate and locomotor activity [13]. Furthermore, these ligands were unable to replace each other to prevent withdrawal symptoms in dogs that had been chronically treated with one of the compounds. 

Most of the haemodynamic effects of opioids are related to decreased central sympathetic outflow, specific vagal effects or, in the case of morphine and pethidine, histamine release. Fentanyl and its analogues do not cause histamine release. All opioids, with the exception of pethidine, produce bradycardia by actions on the afferent fibres of the vagus and the nucleus tractus solitarius and nucleus commissuralis, which have very high densities of opioid receptors. Pethidine often produces tachycardia, possibly due to its structural similarity to atropine. In isolated heart or heart-muscle preparations, opioids produce a dose-related negative inotropic effect, but only at concentrations 100 to several thousand times those found clinically. 

Schlosser B, Kudernatsch MB, Sutor B et al (1995) Delta, mu and kappa opioid receptor agonists inhibit dopamine overflow in rat neostriatal slices. Neurosci Lett 191 126-30 Schwertfeger E, Klein T, Vonend O et al (2004) Neuropeptide Y inhibits acetylcholine release in human heart atrium by activation of Y2-receptors. Naunyn-Schmiedeberg s Arch Pharmacol... 

Similar to opioid receptors, endogenous stores of opioid peptides have been found in the heart [17,18]. The heart has the ability to synthesize all three major types of opioid peptides including enkephalins, endorphins, and dynorphin [19,20]. Howells et al. [21] showed that preproenkephalin mRNA was the highest in rat ventricular tissue as compared to other organs, including... 

Interestingly, morphine is primarily considered to have selective effects on the mu opioid receptor for its analgesic effects however, there is also evidence that it possesses effects on delta or kappa opioid receptors and that crosstalk can occur between mu and delta opioid receptors [44]. To test the hypothesis that the cardioprotective effects of IPC and morphine were acting via a delta opioid receptor, Schultz et al. [45] administered the selective delta receptor antagonist naltrindole to rats prior to IPC or morphine infusion. In both instances, the cardioprotective effects of morphine and IPC were completely abolished at a dose of naltrindole that had no effect by itself on infarct size in nonpreconditioned rat hearts. These data clearly suggest that both IPC and morphine are exerting their cardioprotective effects via the delta opioid receptor in the intact rat heart. 

A final series of experiments were performed in our laboratory to determine the role of the sarcolemmal KATP (sarcKATP) channel and the mitoKATP channel in TAN-67-induced cardioprotection in the intact rat heart [60]. Administration of the selective sarcKATP inhibitor HMR 1098 prior to TAN-67 did not significantly block the cardioprotection produced by TAN-67. Elowever, pretreatment with 5HD, the selective mitoKATP channel blocker, completely abolished TAN-67-induced cardioprotection. These data clearly suggest that delta, opioid receptor-induced infarct size reduction is mediated by the mito KATP channel in rats. A summary of the major signaling components involved in acute opioid-induced preconditioning is schematically depicted in Figure 2. 

Dual inhibitors also demonstrate other therapeutical benefits. They reduced the coronary vasoconstriction in arthritic hearts in a rat model [101], and significantly decreased angiotensin II-induced contractions in human internal mammary artery [102], Opioid receptor activation can cause a presynaptic inhibition of neurotransmitter release mediated by LOX metabolites of arachidonic acid in midbrain neurons. The efficacy of opioids was enhanced synergistically by treatment of brain neurons with COX and LOX dual inhibitors. This report might lead to development of CNS analgesic medications involving combinations of lowered doses of opioids and COX/LOX dual inhibitors [103]. The COX and 5-LOX dual inhibitors also can prevent lens protein-induced ocular inflammation in both the early and late phases [104]. 

Endogenous opioid peptides are increased in myocardial ischemia. Their effect is mediated through presynaptic and postsynaptic mechanisms. Opioids limit the release of stimulating catecholamines by its presynaptic action while opioid receptor agonists act via Gi -linked pathways postsynaptically and alter myocardial channel activity and intracellular activities of protein kinases. Table 1. Figure 10. Blockade of 5 and x-opioid receptors reduced the tolerance of the isolated rabbit heart to ischemia and reperfusion.105 Furthermore, blockade of 8-opioid receptor abrogated the ischemic preconditioning mediated cardioprotective effect while activation of 8-opioid receptor by morphine decreased infarct size and apoptosis in a rabbit model of coronary occlusion and reperfusion.106... 

Figure 3. A diagram showing that bradykinin and opioid receptors precondition the rabbit heart through a pathway dependent on mKm, opening and oxygen radical production, while adenosine receptors do not. Yet all 3 receptors depend on PtX to mediate the protection. Note that everything prior to radical production is a trigger, while PKC acts as a mediator.

J. E.J. Schultz, E. Rose, Z. Yao and G. J. Gross, Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts, Am J Physiol 268, H2157-H2161, (1995). 

Opioid receptors play an important role in the cardioprotective effect of ischaemic preconditioning in the rat heart (Schultz et al. 1998). 

The NEP and APN levels are moderate on heart [74,75] while the concentration of both peptidases is higher in vascular endothelium or vagus nerve terminals [76-78]. However, the mechanisms and site of action (central or peripheral) involved in the cardioprotective effects of the endogenous opioid peptides remain unknown. Nevertheless, owing to their lack of narcotic effects, inhibition of endogenous enkephalin catabolism and subsequent stimulation of delta receptor could have interesting clinical applications in the cardiovascular domain. 

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