Exercise and Endogenous Morphine Release

[kidamnesiac]

^that's a hell of a standard deviation in their distances run in 2 hours!

One reason that naloxone may not work is that the endorphins/enkephalins are just that much tighter binders (so the antagonists just don't effect their binding ability).

 

[seep]

^that's a hell of a standard deviation in their distances run in 2 hours!

Nah. A slow jog'll move you 5k in 30 minutes.

The Wikipedia article everyone's quoting has a lot of misleading links and overlooks a great deal of pertinent work on this subject. Case in point:

Opiate receptor blockade by naltrexone and mood state after acute physical activity.

Daniel M, Martin AD, Carter J.
School of Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.

Acute mood changes occur with various forms of physical activity. Increased levels of endogenous opioids (endorphins) in response to exercise may mediate activity-induced shifts in mood state. Thirteen female and six male aerobics class participants aged 20-46 years received the opiate receptor antagonist naltrexone and a placebo in randomized, double-blind crossover fashion on two separate occasions at the same 75-min high-intensity aerobics class. Mood states were assessed before and after each class, which were spaced 5 days apart, using the Profile of Mood States questionnaire (POMS), a mood adjective checklist, and a Visual Analogue Scale (VAS) which measured mood in relation to several emotional extremes. Mood changes over the course of each aerobics class were compared in the naltrexone and placebo groups. For men and women, significant differences between conditions were observed in overall mood by both the POMS (P less than 0.005) and VAS (P less than 0.02). There were significant differences between conditions for most subscales of each mood instrument (P less than 0.05); with the placebo, mood states became calmer, more relaxed and pleasant, tending away from depression, anger and confusion. Positive mood shifts did not occur when subjects were preloaded with naltrexone, suggesting that activity-generated mood changes are mediated through endorphinergic mechanisms.

 

[Hammilton]

no kidding.

except that naloxone is capable of blocking them, as we see in some studies.

I don't like the study cited above for a couple reasons, but it's mostly a general distrust of these PET scan studies (and the like). They seem like the new phrenology.

What I don't understand is how the better studies (more participants) find no connection but the smaller studies seem to.

I've not had naloxone, or rather, I've not had naloxone where it would do anything, however, is it the case that naloxone produces subjective effects? I'm wondering if the subjective effects it produces give it something of an active placebo quality that gives it a benefit above the inactive placebos, because even in the studies that find activity, it's only active against mood and euphoriant effects of the runners high, not the hypoalgesic effects it produces.

Which, if endorphins are the primary mediating factor, and based on the whole theory behind it, blocking the endorphins should block the pain relief of the runners high. But naloxone has no effect in any study on this aspect of the high. WTF does this mean?

I hope I'm explaining myself well, I'm getting rather tired, and this is something that wraps itself around and around, it seems.

 

[seep]

^I'm actually pretty stunned that what's been observed is that opioid receptor blockade negatively affects mood (after physical stress) but seems to have no effect on pain perception. This is exactly what you're squinting at, right: that interfering with the work the body does to counteract pain has no effect on pain, but rather on mood?

The German study uses a nonselective ligand instead of a competitive antagonist. The Daniel/Martin/Carter study uses the competitive antagonist but measures results by questionnaire. Inadequacy of measurement tools aside, if the data measured in these and other trials implicate b-endorphin in post-exercise euphoria but discount its role in analgesia during and after exercise (contrary to what I expected), what is the CNS actually doing during moderate rises in physical stress? Two asterisks that immediately come to mind:

1) Are the bodies of exercisers non-inertial reference frames? An older experiment seems to hint at this:

http://www.ncbi.nlm.nih.gov/sites/entrez

I don't think anyone has retested this, but what's fascinating is that mu-receptor blockade exhibits predictable results on subjects that are cognitively stressed (self-efficacy is more closely related to emotion than athletic ability is; to what extent is pain dependent on cognition?).

2) Endorphin has only been studied for 30 or so years and its structural similarity to morphine at the binding site may have blinded researchers to many other factors. For processes that don't involve heavy breathing, endorphin may be little more than an intermediate messenger (marker) for a number of metabollic processes (a cheerleader who can also do CPR).

 

[nabollocks]

Ok... this is not exactly science but here goes.

I have a knee condition that gives persistent pain, day and night.

I take a daily dose of pain killers.

If I ride my bicycle or swim for 1 hour a day my pain is reduced by ~50%. (This means less medication, and a clearer mind)

Like I said, not science... but its the truth.

If I had to compare it to drugs I would probably say the following:

1 hour exercise = 5mg oxycodone = 100mg tramadol = 10mg morphine. (This is a prolonged pain relief)

Exercise has the added benefit of keeping my tolerance in check.

 

[...]

I don't have time to find particular references right now... but the idea that endorphins as meaningful in the cognitive effects of exercise is not supported very well. The increase in beta-endorphin (and other endogenous opioids) is just as, if not less impressive than the increase in 5-HIAA/5-HT, anandamide, DA, and adrenaline. Not only this, but naloxone/naltrexone do NOT block the cognitive effects of exercise. This suggests that endorphins play little (if any) role in the desired effects.

Wives tales don't make a good basis for speculation.

Apologies for necromancing this thread, but I am writing a paper on this topic. Does anyone have references for the claim that the runner's high is not blocked by naloxone/naltrexone administration? I cannot find them. All I can find are people talking about specific experimental results, but not the results themselves.

 

[serotonin2A]

Apologies for necromancing this thread, but I am writing a paper on this topic. Does anyone have references for the claim that the runner's high is not blocked by naloxone/naltrexone administration? I cannot find them. All I can find are people talking about specific experimental results, but not the results themselves.

I don't have the references handy, but be aware that there isn't really any evidence that strongly supports the endogenous opioid system playing a role in the rewarding effects of exercise. It was more that once endogenous opioids were discovered, there was a tendency to link any endogenous reward process to them.

Recently, substantial evidence has emerged linking the endocannabinoid system to the "runners high". For example:
http://www.ncbi.nlm.nih.gov/pubmed/22442371
http://www.ncbi.nlm.nih.gov/pubmed/19020416
http://www.ncbi.nlm.nih.gov/pubmed/24148812

 

[...]

It does not feel like a cannabinoid at all, at all. I don't really know what to compare it to, actually.

 

[endotropic]

It does not feel like a cannabinoid at all, at all. I don't really know what to compare it to, actually.

Localized intermittent vs. systemic continuous cannabinoid activation will produce drastically different feels.

 

[...]

There's also now the kynurenine pathway, which I learned about this morning. Can you imagine a peripherally acting anti-depressant?

Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier.

http://www.cell.com/cell/abstract/S0092-8674(14)01049-6

Seems like what we know is much less than what we don't know.

 

[...]

In my research I am finding the opposite of what was earlier claimed in this thread. Naloxone does indeed block the reinforcing properties of exercise in rats:

http://psycnet.apa.org/journals/pha/19/6/389.html

Exercise reinforcement in steroid users is mediated by beta endorphin:

http://www.sciencedirect.com/science/article/pii/S0376871614007844

I have had to change my hypothesis.

 

[serotonin2A]

In my research I am finding the opposite of what was earlier claimed in this thread. Naloxone does indeed block the reinforcing properties of exercise in rats:

http://psycnet.apa.org/journals/pha/19/6/389.html

Exercise reinforcement in steroid users is mediated by beta endorphin:

http://www.sciencedirect.com/science/article/pii/S0376871614007844

I have had to change my hypothesis.

Neither of those studies shows that endorphins are responsible for the rewarding effects of exercise. In the first study, anything that reduced the rewarding effect of exercise should have reduced the breakpoint (how hard the animals will work to be able to exercise). If something is no longer pleasurable, the animals won't work as hard to do it. Naloxone did not effect that. Measurements of response rates and revolutions can be effected by many things besides reinforcement. Maybe the animals felt sick after naloxone and could no longer run?

In the second study, exercise was correlated with endorphin levels. Fair enough. But it is probably correlated with a whole number of things that have no involvement in euphoria. That isn't evidence that beta-endorphin plays a role in the rewarding effects of exercise. And they didn't administer naloxone.

 

[...]

Thank you for clarifying that!

I *want* to dismiss the endorphin hypothesis, but I can't honestly find sufficient evidence to do so, and all the evidence seems to point in the opposite direction.

The bottom line to me is, there are a variety of endogenous substances that are trying to get us to exercise, and beta-endorphin *seems* to be one of them.

It would be cool to be proven wrong here, because the endorphin-rush thing is deeply ensconced in our culture. I believe it is the only neuropeptide that has mass-media notoriety. Here are some mentions of "endorphin" in the news just in the past month:

A week-long "holiday" of nothing but hard exercise might not sound appealing - but one amateur triathlete found it provided exactly the endorphine fix he wanted.

I got music in me, yo. And singing creates an endorphin rush that all you non-Basics are missing out on.

The evening's tone is set and sustained by Mr. Jones and Ms. Nielsen, who waltz through the show with the secret but infectious smiles of people listening to unheard, endorphin-boosting strains.

In fact, I am a very bad runner. I don’t get that endorphin high from a run. I don’t skip out of the door at the thought of clearing my head with a jog along the river.

But believe it or not, getting in your exercise can help improve your studies and make you feel better overall. It’ll give you extra energy to focus on your work, tone up your muscles, help you sleep better, make you happier (because it releases endorphins) and give you a chance to get some fresh air.

 

[serotonin2A]

Thank you for clarifying that!

I *want* to dismiss the endorphin hypothesis, but I can't honestly find sufficient evidence to do so, and all the evidence seems to point in the opposite direction.

The bottom line to me is, there are a variety of endogenous substances that are trying to get us to exercise, and beta-endorphin *seems* to be one of them.

It would be cool to be proven wrong here, because the endorphin-rush thing is deeply ensconced in our culture. I believe it is the only neuropeptide that has mass-media notoriety. Here are some mentions of "endorphin" in the news just in the past month:

There is definitely a popular misconception that endorphin is responsible for the rewarding effects of exercise. Many people think that tomatoes are vegetables, but that doesn't change the fact that they are a fruit. Unfortunately, most people don't read the current literature about neuroscience.

In terms of why you reached the conclusion that you did, can you list the specific evidence (scientific studies) showing that endorphins are responsible for the rewarding effects of exercise?

In my mind, you would need to show: (1) that people taking naloxone or naltrexone no longer experience any reward from exercise. And you would want to see the same thing from people on opioid maintenance therapy because chronic methadone and buprenorphine should drastically reduce the ability of endorphins to activate the mu-receptor. (2) PET data showing that the number of free (unoccupied) mu-receptors declines in people who have exercised and who are experiencing "runners high". (3) Data from animals showing that during and/or after exercise, endogenous opioids are released locally in regions of the brain that are involved in reward processes. (4) That exercise is not rewarding in mice lacking mu-receptors (knockout mice), or in animals that lack endorphins.

 

[...]

This forum is among the best things on the internet. Nowhere else can I raise this topic of discussion and get replies with such a level of sophistication.

In my mind, you would need to show: (1) that people taking naloxone or naltrexone no longer experience any reward from exercise. And you would want to see the same thing from people on opioid maintenance therapy because chronic methadone and buprenorphine should drastically reduce the ability of endorphins to activate the mu-receptor. (2) PET data showing that the number of free (unoccupied) mu-receptors declines in people who have exercised and who are experiencing "runners high". (3) Data from animals showing that during and/or after exercise, endogenous opioids are released locally in regions of the brain that are involved in reward processes. (4) That exercise is not rewarding in mice lacking mu-receptors (knockout mice), or in animals that lack endorphins.

There's a study in this thread that does #2 (post 20). I don't know if the other scenarios have been tested. #1 seems like an obvious experiment to conduct, and lots of people (and Wikipedia) talk as if such an experiment has been conducted, but I can't find it anywhere.

It seems the current logic is:

1) Endurance exercise causes pleasant feelings in exercisers for several hours afterwards.
2) Serum beta endorphin levels rise during and after endurance exercise.
3) Opioids cause pleasant feelings.
4) Thus it's reasonable to believe beta endorphin is at least partly responsible for the pleasant feelings endurance exercise produces.

 

[serotonin2A]

That's a good start, but there is still the matter of showing that endorphins mediate the effect on binding.

Beta-endorphin and ACTH are released in response to stress, so it makes sense that plasma levels would rise after exercise. But whatever neurochemical(s) are involved in the rewarding effects are probably released locally in specific brain regions, rather than into the circulatory system. Beta-endorphin has trouble partitioning into the brain, at least at levels that are psychoactive, so it doesn't make sense to release it into plasma if the goal is to produce an effect in the brain.