The heart is a complex neuroendocrine (opioids, NPY, VIP) or mechanoendocrine (ANP) organ. Opioid peptides and receptors are present in the heart and nerves such that they can easily modulate cardiac function. Cardiac opioids may have autocrine, paracrine and endocrine function. The challenge is to find the signal that turns them on and then what they do in the face of an overwhelmingly redundant system making knock-out technology hard to interpret. Determining the cardiac release of opioids in an intact system still requires a larger animal model.