Pain has long been recognized as one of the cardinal symptoms of myocardial ischemia and myocardial infarction. The adaptive significance of this pain has been unclear. If anything, pain was thought to motivate people to lie down and rest, which would reduce oxygen consumption and might relieve their ischemia. But the pain of myocardial ischemia is exceptionally severe, much greater than would be needed to induce most of us to stop what we were doing and rest. Because the pain of myocardial ischemia is so severe, it is often treated with morphine. Several years ago, Trip Meine and colleagues reported a non-randomized, retrospective study which showed that patients with a particular form of myocardial ischemia (technically, without elevation of the ST segment in their electrocardiograms) who had been treated with morphine had higher mortality than did patients who were not given morphine (Meine et al. 2005). This intriguing finding has not yet led to a randomized, controlled study of morphine in myocardial ischemia, and people with myocardial ischemia and pain are still treated with morphine. A recent study by Silvia Amadesi and colleagues now suggests a mechanistic basis for the role of nociceptive sensory pathways, if not pain itself, in healing damaged ischemic tissues (Amadesi et al. 2012). Substance P is a neuropeptide that is released from sensory neurons in response to noxious stimuli. Amadesi et al. showed that acute myocardial infarction in mice was accompanied by a rise in substance P, which led to the activation and mobilization of progenitor cells from bone marrow. These progenitor cells migrate to ischemic tissues, where they promote angiogenesis and increase blood flow. The administration of morphine blocked all of these responses. Mice, of course, may not be good models for humans. Amadesi and colleagues did, however, demonstrate some steps in this pathway in humans. People with heart attacks had elevated levels of substance P and of cells that had some of the characteristics of progenitor cells. We don’t know, though, if these cells increase vascularization and blood flow in human myocardium. There are still many puzzles in this story. Is the pain of myocardial ischemia itself useful or is it a side effect of the activation of nociceptive neural pathways? Pain is a much less frequent symptom of myocardial ischemia in women than it is in men. Does the absence of pain affect the mobilization of precursor cells and the revascularization of ischemic tissues? Myocardial infarction is not thought to have been an important cause of death in traditional human societies. Did this pathway evolve as part of a general mechanism that promotes angiogenesis in ischemic tissues? Although we still have much to learn, these new results suggest that, at least in some clinical settings, pain (or the activation of nociceptive pathways) may be an adaptive response that promotes recovery from injury. In these settings, the routine administration of analgesics may be harmful.


Amadesi, S., et al. 2012. Role for substance P-based nociceptive signaling in progenitor cell activation and angiogenesis during ischemia in mice and in human subjects. Circulation 125(14):1774-86.
Meine, T. J., et al. 2005. Association of intravenous morphine use and outcomes in acute coronary syndromes: Results from the CRUSADE quality improvement initiative. Am Heart J 149(6):1043-9.