Physical Activity and Brain Health – Part 2

Physical Activity and Brain Health – free full-text PMC6770965/ – Genes (Basel).  Sep 2019 – continued from Part 1

Exercise-Dependent Production of Dopamine, Endocannabinoids, and Opioids: Effects on Mood, Analgesia, and Happiness

In addition to an improvement of body fitness and learning and memory skills, it is well documented that PA (Physical Activity) can induce changes in the mental status, reducing anxiety and producing a general sense of wellbeing.

Moreover, it can induce analgesia.

Really? When I engage in physical activity, it’s usually a painful endeavor. If I didn’t enjoy some activities so very much, like hiking, bicycling, and dancing, I can’t imagine I’d have the will to do them.

When my body reacts with increasing pain all during an activity it feels like it’s trying to make me stop doing these activities I love. I can push against the pain only so long before I’m miserable and have to stop. I wonder how much longer I’ll be able to force myself to get on a bike…

The worst part is that, because my physical activities hurt so much, I’m being punished for doing them.

The precise mechanisms involved are not yet completely understood but a few molecules, probably acting in synergy, have been identified and are currently studied as possible mediators of these further effects of PA.

5.1. Dopamine

Dopamine (DA) producing neurons are present in distinct areas of the cerebral cortex, but are mostly concentrated in the ventral midbrain, where they are arranged in different nuclei.

DA neurons appear to form a brain network regulating the motivational behaviour of animals, allowing them to learn the difference between useful and harmful things, and consequently to choose proper actions.

DA also seems to be necessary for performing motivated actions to achieve goals, as demonstrated by the unsuitable behaviour of dopamine deficient mice.

In the mammalian central nervous system, DA controls many processes, such as feeding and locomotion; it is also involved in the mechanisms of cognition and ‘adaptive’ memory formation, influencing the hippocampal long term potentiation (LTP), and upregulates BDNF in the prefrontal cortex.

As mentioned, a lot of different evidence demonstrates that the mammalian brain is capable of changing its functional and structural characteristics to adapt to the ever-changing surrounding world.

This is achieved by learning and acquiring skills, thus improving cognitive functions. Neuroplasticity is orchestrated by several neurotransmitters and neurotrophins, and many cues indicate that exercise has an important role in its regulation. 

In particular, DA regulates emotion and reward-related brain functions, and many authors have postulated that the positive properties of PA may be due to its ability to increase DA concentration.

Interestingly, PA increases the concentration of the same neurotransmitters, including DA, also activated by some drugs and alcohol, and this could be the reason why it improves mood in humans.

Moreover, PA, and specifically voluntary exercise, creates a sharp increase in DA concentration, and has a strong positive effect in overcoming aversion.

This is the first hint I’ve seen that it matters whether exercise is voluntary or involuntary, even at the biochemical level. This would explain why forced exercise has a completely different effect than exercise done voluntarily.

My question is then what exactly defines the difference between “voluntary” and “involuntary” exercise, and whether being forced to exercise by others is really different from forcing ourselves to exercise.

I wonder if they stress the voluntary part because there’s a biological difference seen for involuntary exercise, and how “voluntary” exercise has to be to generate these benefits.

I couldn’t contain my curiosity, so I just spent a couple of hours poking around in PubMed searching for “voluntary exercise” versus “forced exercise”. To my surprise, there are clearly different biochemical responses to these two modalities, so stay tuned for future posts exploring this phenomenon.

This has implications for the blanket recommendation of “exercise” for all kinds of pain or mood or physical maladies.

One interesting aspect of DA function is that it appears as one of the factors that distinguish physically active organisms from inactive ones, influencing the locomotory activity and even the tendency of the individuals to engage in PA.

Voluntary exercise is genetically controlled and depends on different neuromodulators, including DA itself.

This might be because voluntary exercise recruits different brain regions and some level of desire while involuntary exercise is just unpleasant and stressful.

The implication is that involuntary exercise is a dud.

Given the enhancing effects of PA on DA production and release in the brain, it can be hypothesized that anauto-sustaining circuit exists by which DA and PA positively interactthe more DA an individual animal produces, the more it is prone to live actively, and the more DA will be consequently released in this feed-forward system.

In summary, PA may cause an increase in serum calcium levels, and calcium can stimulate dopamine synthesis in the brain.

A possible mechanism leading to calcium increase in the brain could be the release of lactate following exercise. This may induce, in turn, an increase of blood acidity that could activate parathyroid hormone, or directly increase calcium concentration by favouring bone resorption.

5.2. Opioids, Endocannabinoids, Analgesia, and the “Runner’s High”

The endogenous opioid system includes different peptides (i.e., endorphins, enkephalins, and dynorphins) that derive from larger precursors and bind to G protein-coupled receptors.

Three main receptors (μ, κ, and δ) mediate analgesic effects of these molecules.

Several studies have demonstrated PA-dependent increase of circulating opioids, and in particular of β-endorphin, in relationship with the intensity of exercise, and this β-endorphin increase correlates with analgesic effects both in humans and in rodents.

Many studies, however, suggest that opioids are not the only molecules involved in analgesia induced by exercise. For example, activation by exercise of the mesolimbic system in rodents has been also related to analgesic effects.

The endocannabinoid system (ECS) includes two G protein-coupled cannabinoid receptors (CB1 and CB2), widely expressed all over the body, and their endogenous ligands, the most well-studied of which are two derivatives of the arachidonic acid.

An expected consequence of these ECS functions is increased production of endocannabinoids in response to exercise that induces higher energy utilization.

This is a grammatically ambiguous statement:

  • does the increased production of endocannabinoids induce higher energy utilization during exercise? 
  • does higher energy exercise lead to increased production of endocannabinoids?

A variety of studies have indeed shown PA-dependent increase of circulating endocannabinoids, even if the results significantly differ from one study to another.

Interestingly, it was also reported that hypoxia potentiates ECS activation, and it was suggested that the muscles can be the main source of the exercise-induced increase of circulating endocannabinoids, that then can cross the BBB.

Overall, the levels of circulating endocannabinoids are

  • inversely related to anxiety and depression, and
  • positively related to BDNF concentration and, thus,
  • to the beneficial effects on mood and to a sense of vigour and wellbeing.

Since the 1960s, it was known that long-running could cause what was called the “runner’s high”, a sudden sense of euphoria and wellbeing, accompanied by analgesia.

I’ve been athletic all my life, yet I have never experienced a runner’s high. As I hike or bike,

  • my pain increases,
  • my fatigue increases, and
  • my enjoyment decreases.

There is none of the promised magical “runner’s high“, except the sense of accomplishment and the enjoyment of moving freely outdoors.

For a long time, exercise-dependent production of endorphins was considered responsible for at least the analgesic component of the runner’s high. More recently, as mentioned, the involvement of both opioids and endocannabinoids in this aspect of the response to PA has been consistently reported, and, in addition, it was found that cannabinoid-agonists can enhance the release of endogenous opioids in the brain.

We can thus infer that the two systems act in synergy in the anti-nociceptive effects of exercise.

It was also suggested that mood improvement could relate to PA-dependent increase of the levels of neurosteroids, and in particular of dehydroepiandrosterone (DHEA), a molecule with a variety of effects on different neurotransmitter receptors, such as

  • the GABAA receptor, and
  • the NMDA as well as the
  • AMPA receptors for glutamate.

I’ve posted several times about the benefits of neurosteroids like DHEA, which can be augmented by supplements. (see

6. Conclusions and Perspectives

In conclusion, habitual exercise has a variety of positive effects on the human body, from regulating cardiorespiratory and cardiovascular fitness, to improving glycaemia and insulin response.

In addition, as discussed, it is a way of maintaining not only a healthy body, but also a healthy mind, at any age. In particular, it can represent a non-pharmacological (and sometimes enjoyable) strategy to delay the effects of both physiological ageing and pathological neurodegeneration on brain health.

However, although exercise prescriptions (including frequency, intensity, type, and time) were given, for example, for individuals with hypertension, we cannot yet refer to specific exercise prescriptions for maximizing the positive effects of PA on cognition.

PA induces, a variety of cellular and molecular effects, both in the periphery and in the brain.

As we have seen, every molecule/group of molecules probably affects different aspects of brain function, but their synergic effects contribute to brain health as a whole.

Among all these factors a key role seems to be played by BDNF.

Notably, all these effects also depend on the physical pre-exercise conditions of each person.

What? So exercise might not help people who are already fit?

In this context, an additional issue arises from the actual difficulties of old people and patients with neurodegeneration to perform voluntary exercise. 

This is also a severe problem for people in pain. When my hip joint is screaming in pain, it would be almost impossible to force myself to go walking. And, it brings up the question of whether I even should be walking when a joint is signaling a severe problem. With EDS, it’s usually subluxing that causes such pain.

Exercising muscles around a joint that isn’t properly aligned will only cause further damage.

Interestingly, a recent paper reported that neuromuscular electrical stimulation (NMES) can increase BDNF and lactate serum concentration even more than voluntary exercise, and might thus represent a solution for individuals who cannot engage in high-intensity exercise or are even unable to perform any exercise at all.

This is an interesting idea: using electrical stimulation to cause regular muscle contractions. The problem is that there’s no way to trigger that full range of muscle and tissue movements in the body that way even the simplest exercises do.

Notably, we are now aware that pharmacological therapies should be ideally shaped on individual patients because of genetic and epigenetic differences affecting responses to the drugs.

This awareness considered self-evident by most science-minded folks, but is completely foreign to all the people and agencies that insist we all take standard doses of opioids.

When talking of physical activity, tailoring prescriptions to individuals is even more difficult since the ability to perform exercise as well as the exercise outcomes likely depend on a wider set of genes (and their epigenetic setting).

These considerations become much more stringent when we focus on the nervous system—every brain is unique because of genetic and epigenetic peculiarities that accumulate throughout our lives, as an effect of learning and experiences that sculpt our mind.

So they won’t even consider prescribing standard exercises because of individual differences, yet have no problem insisting on “standard doses” of opioids.

as life expectancy is increasing all over the world, it is of the utmost importance for all of us to maintain independence in the daily life activities and a sense of wellbeing as long as possible.

This is certainly true, but without opioids to ease the pain I suffer with physical activity, I could not exercise. So, denying a patient opioids has ripple effects when activity levels can no longer be maintained.

Without opioids, I would exercise much less and no longer achieve all the benefits I’ve been getting from all my physical activity.

This seems like just another layer of cruelty caused by forced opioid tapers.

Since PA can clearly contribute in ameliorating physical fitness as well as the mental status, it should be a social and political task to promote the conditions that allow the realization of physical exercise programs for the entire population, and especially for the elders and for children.

In particular, we suggest that both healthy people and patients are encouraged by physicians to perform physical activity, underlining the higher impact and efficacy of moderate and regular exercise, in comparison with acute and heavy bouts of activity.

This post is a continuation of  Part 1

2 thoughts on “Physical Activity and Brain Health – Part 2

  1. Kathy C

    The current nonsense about “exercise” appears to be contributing to the epidemic of despair, obesity and diabetes in the US. The sugar industry got physicians to endorse “exercise” instead of cutting back on sugary drinks and processed foods. In general exercise is beneficial, but when it is forced, it seems to backfire. In most societies exercise is part of every day life, it is not separate from every day activities. Beneficial activities, like walking, gardening, and others offer opportunities for the benefits of social interactions. This is not the case in the US, where cars dominate and people live in social isolation.

    The approach to exercise is backwards, and designed to belittle and humiliate people with limitations. Physicians recommend exercise, because the industries presented it as an acceptable alternative, to nothing. The exercise dogma, does not take into account physical limitations, environment, or circumstances. It is a platitude, meant to cover for the many failings of our corrupt system. People that live in food deserts, or only have access to processed foods, can be discriminated against for their poor health. People with serious obesity issues, are just “lazy” because they do not exercise. Blue collar workers, who do physical work, can be blamed for their injuries because they do not have the time or energy, are not “exercising” even though their jobs are physically demanding.

    Like everything else in our corrupt system, exercise and wellness have been weaponized. For a lot of people the accepted form of “exercise” is joining a gym. Often these people give up, because they get injured, or the costs and time are not paying off. People in many neighborhoods are not comfortable walking, often the only place to walk is next to 6 lanes of traffic, through bleak suburban hellscapes. Exercise is a way to blame people for their poor health, instead of the various industries that are profiting.



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