Pure Pedantry

ResearchBlogging.orgWe have all heard about the runner’s high, and a great many of us have felt it. When you are running a marathon, about an hour or two in you feel a feeling of euphoria right like you could run forever. Of course you can’t, but you don’t feel that way. (In my case the runner’s high immediately precedes the runner’s heart attack.)

It is still not entirely clear what causes the runner’s high, but Boecker et al. have taken a big step in explaining it using PET scanning.

The prevailing theory is that the runner’s high is caused by endorphins. Endorphins are endogenous opioid neurotransmitters that bind to the same receptors that are bound to by drugs such as heroin and morphine. Endorphins in the CNS are involved in a lot of things, but most importantly they modulate pain perception.

The endorphin theory of the runner’s high was based on a couple observations.

These findings implicate the endogenous opioid system in producing the runner’s high. However, what we would really like to do is confirm that more endorphins are binding in the brain during the high and that this binding correlates with the good feelings.

This is exactly the experiment that Boecker et al. perform, publishing in the journal Cerebral Cortex.

To show this, Boecker et al. use a technique called positron emission tomography (PET). For those of you who don’t know, PET works by injecting a radioactive tracer molecule into the blood. When this tracer undergoes radioactive decay it releases a positron that shoots out and can be detected. By putting the person’s head in a special detector, the direction of the emitted positrons can be used to triangulate their origin in the brain. This allows the scientists to determine the relative concentration of the tracer at different points inside the brain.

At this point the selection of the tracer becomes very important. You could use a tracer that just equilibrates throughout the brain, but you would find nothing important. Instead you want to use a tracer whose relative concentrations are modified by brain activity or metabolism. Examples include radioactive glucose molecules that can become concentrated in brain areas that are metabolically active.

The tracer used in this experiment is a drug that binds non-specifically to opioid receptors. (There are actually three different types of opioid receptors, and this drug does not attempt to distinguish them.) The ligand is called 6-O-(2-[18F]fluoroethyl)-6-O-desmethyldiprenorphine ([18F]FDPN). The radioactive isotope for this tracer is a atom of 18F which will decay and release the positron. (This is a pretty common isotope to use in PET because fluorine can be substituted for a hydrogen in whatever molecule you would like to use.)

The theory for how this works is that the tracer binds to opioid receptors in the brain. Then as endogenous opioids like endorphins are released, they displace the tracer from those receptors leading to a relative reduction of the concentration of tracer — and hence positrons emitted — from that part of the brain. Key point here: endorphin release in this experiment are measured as reductions in the tracer signal.

The authors measured the resting endorphin activity in the brains of 10 athletes using this system. They then sent the runners out on a 2 hr run. After they returned they put them back in the scanner and looked at endorphin activity again. They compared the images before and after the run to look for what areas of the brain had greater endorphin activity (less signal from the tracer). This produced a list of several brain regions that had increased endorphin activity. Then they asked the subjects to rate how euphoric they felt. They correlated the feelings of eurphoria with the changes in the regional activity to find which regions correlated best with euphoria.

They found that several regions increased endorphin activity during exercise AND correlated with reported feelings of euphoria:

Changes in central opioid receptor binding after 2 h of long-distance running were identified preferentially in prefrontal and limbic/paralimbic brain regions. Specifically, the perceived levels of euphoria were inversely correlated with opioid binding in prefrontal/orbitofrontal cortices, the anterior cingulate cortex, bilateral insula, and parainsular cortex, along with temporoparietal regions. (Emphasis mine.)

These results are depicted below for (starting from the top) the anterior cingulate (ACC), the orbitofrontal cortex (OFC), and the insular cortex (INS). On the right shows the changes in activity. On the left shows the correlation between changes in signal among the subjects and reported euphoria; see how the two are inversely correlated. (Figure 4 from the paper)


The regions that they found activated during the runner’s high are not all that surprising. Many of these regions — particularly the OFC — have been implicated in perception of reward in many other contexts.

This result provides further evidence that the runner’s high is caused by endogenous opioid release in the brain. What is interesting to me is that you see similar brain activation for a variety of different types of rewarding events — whether they be drugs or video games or anything. I seem to remember that they even showed that in academics these parts of the brain are activated when they learn! This similarity of reward activation in a variety of behavioral contexts implies two things: a common system for analyzing rewards and a wide variety of things that humans have found to activate this system. It would appear that it really is “whatever floats your boat” that you find rewarding.

OK, so maybe this is one of those “OMG they showed something obvious with imaging” studies, but I still think it is pretty cool. It looks like the description of it as a runner’s high was…well…accurate.

Boecker, H., Sprenger, T., Spilker, M.E., Henriksen, G., Koppenhoefer, M., Wagner, K.J., Valet, M., Berthele, A., Tolle, T.R. (2008). The Runner’s High: Opioidergic Mechanisms in the Human Brain. Cerebral Cortex DOI: 10.1093/cercor/bhn013


  1. #1 caynazzo
    February 28, 2008

    As a runner and a biologist, I agree–totally cool. However, I’m more curious as to what’s going in the brain when you “hit the wall.” That is, somewhere between mile 19 and 23 for most athletes a strong depression-like state sets in.

  2. #2 Jake Young
    February 28, 2008


    I was thinking about that and I honestly don’t know. It is possible that there is a threshold of tiredness before which endorphins can make you feel fine but after which you are going to feel bad.

    I will look into it to see if there is any research about that.

  3. #3 natural cynic
    February 29, 2008

    The wall is probably due to several factors:

    Muscles use two major sources of fuel during endurance exercise, fat and glucose. There alsawy is enough fat around to supply energy for many more miles, but the muscle glycogen is limited. Glycogen depletion in the muscle fibers that are normally used for endurance – the slow twitch and fast twitch with high aerobic potential. When the glycogen concentration goes below a certain amount, the force production in these fibers is reduced and the brain has to recruit more motor units to produce the same effect [maintaining pace]. This makes the brain conscious of the increased effort.

    To replace the glucose that is needed to maintain an even pace, the liver releases glucose from its glycogen stores and starts gluconeogenesis. As muscle glycogen is decreased, a higher proportion of blood glucose is needed to maintain the effort until blood glucose uptake in the muscles [and brain, etc] exceeds glucose production from the liver – producing hypoglycemia and its attendant effects on the brain.

    In addition, prolonged exercise will cause ion imbalances. If too much water and not enough Na is consumed, hyponatremia will ensue, with striking effects on perceptiions. Also, the ability of the saarcoplasmic reticulum in the muscle is compromised – the membranes get a little leaky and, with not enough Ca pumped back during muscle relaxation, relaxation is impaired [and the brain notices]. The excess cytoplasmic Ca may also start to engage Ca-dependent proteolytic systems causing pain. This may be a factor in undesirable changes in the myofibrillar proteins, causing a failure to completely relax when Ca is temporarily reduced during relaxation.

    and probably a few other factors


    The mental effort needed to maintain pace is significantly increased and choices are made to slow down or stop. Training increases the body to store more glycogen in the muscles, use a higher proportion of fat to glycogen for a given effort and allows the brain to overcome all of the negative stimuli that is gets from fatigue.