Biology of opioid withdrawal

[arthunter888]

So I recently became semi-dependent on oxycodone. I experience mild withdrawal on the days I don't use. Fortunately, I am NOT past the point of no-return, and still have the opportunity to restore the health of my internal endorphin/opiod system.

I began researching about why exactly withdrawal occurs. I learned about down-regulation: that when neurons are exposed to EXTERNAL opiates (getting high) on a (semi) regular basis, the opiate receptors on the neurons will decrease in number, AND become less sensitive, in attempt to counteract the effects of incoming opiates, and thus achieve "normal" functioning (being sober).

So now I am trying to up-regulate my receptors. One of the methods for this is obviously abstaining from more opiate drugs. The withdrawal seems to be dragging on forever, so I need additional measures.

A common recommendation is exercise. I don't get the recommended amount. People say that exercise helps one to produce endorphins (internal opiods), which combats withdrawal. This is confusing to me, because as I understand, it's not a lack of endorphins that causes withdrawal; it's a lack of RECEPTORS to which the endorphins attach. Does MORE endorphins around the neurons ENCOURAGE the up-regulation of receptors, or is there a different mechanism at work? While I do not doubt that exercise helps, I'd still like to know the science behind this. What exactly is happening when an opiate-addict exercises?

 

[arthunter888]

You might want to move this to ADD.

Mods, I am okay with this if you see appropriate.

 

[sekio]

Good advice for detoxing from drugs: Don't worry about receptors, worry about feeling better.

Long term opioid abuse leads to an increased population of receptors to combat the temprorary loss of receeptors/sensitivity caused by moderate-term abuse, withdrawal is the result of having too many receptors for your body's natural endorphin production to fill. Excercise helps your body increase production of natural endorphins and helps releive withdrawal symptoms (as well as introducing new positive reward circuits rather than having dope as the only recreation in your life) whereas with time your body downregulates and destroys the excessive receptors on your cells, restoring homeostasis.

Internalization and destruction of receptors also happens to a lesser degree with chronic treatment of e.g. opioid drugs, it expliains the tolerance and loss of efficacy of a drug with continued treatment in the short to moderate term.

This may all be wrong but this is the model I have in my head to conceptualize the process. In layman's terms, first you lose receptors and produce tolerance with continued drug usage (during which the drug is in your blood and actively working on your brain), then your body compensates by making more (after drug treatment ends and you have low blood levels of said drug), leading to withdrawl which is eventually stopped by your body re-adjusting the other direction (after long term abstinence).

Titration downwards works by lessening the "crash" caused by too little natural endorphin production but at the same time allowing your body to slowly re-establish homeostasis.

 

[arthunter888]

This explanation seems a bit messy.

Every source I've checked says withdrawal is from having NOT ENOUGH receptors for natural endorphins to fill. Mild withdrawal from moderate use is the same mechanism as severe withdrawal from heavy use, just at a different extent. Looks like only ADD is going to solve this?

 

[sekio]

I'll move it there.

OD -> ADD

 

[DustnRoses]

To avoid making another thread on a similar subject, I thought I'd piggy back on yours, since I'll already be looking at it frequently. I too wonder about the science regarding exercise and opiate withdrawal. My question is a little more simple. If you are high on opiates, and exert physical energy, whether it's running, playing a sport, lifting weights, etc. what actually happens? Most people say not to, because it makes your body metabolize the drugs faster, thus shortening your high. Is that true? Or can it have a positive effect, like making them kick in faster, or is there no effect at all?

 

[PoppyLlama]

I definitely think that it will shorten your high, however, sometimes exercising on opiates just makes me get ultra high for a shorter period of time instead of high for a longer period of time, you know what I mean?

I also think it can make them kick in faster, because by exercising you are speeding up your metabolism and blood flow, therefore more drug will reach your brain and receptors faster, but will also be metabolized faster.

 

[sekio]

I personally think that moving around increases metabolism only minimally, your liver is pretty active regardless of physical activity.

 

[Nagelfar]

withdrawal is the result of having too many receptors for your body's natural endorphin production to fill.

So, this being the case, and it is percentage of over-all receptors filled (much like I've read with dopamine receptor over-expression from stimulant abuse), being that exogenous opioids are ligands, couldn't a substance be devised that compromises and internalizes opioid *receptors* (without agonism) much like amphetamines phosphorylate dopamine *transporters*, or are receptors too simple of a mechanism to selectively do this without over-all toxicity?

 

[Coolwhip]

Naloxazone is a irreversible antagonist, it will bind until the receptor is absorbed through endocytosis. But I don't know if it actually causes this to occur any more quickly, or if it just block the receptor for the remainder of it's natural cycle.

Also, I'm no expert, but I'm not sure I buy Sekio's explanation. I don't really understand why, or how, your body would produce more opiate receptors in response to constant activation. At least not in great enough number, in the right parts of the brain, to cause the WD we see. I know that some receptor up-regulation is seen in some parts of the brain following moprhine or other agonist administration, but AFAIK this is caused by an increase the production of anti-opioid peptides, such as shorter forms of beta-endorphin and dynorphin. But I don't think that up-regulation has been fingered as the cause of WD.(although the anti-opioid peptides themselves have been, after the exogenous ligand is cleared the anti-opioid peptides are still there working)

Although I could see there being epigenetic factors at play here, like the over and under expression of certain genes caused by opiate use causes any new receptors that are created after/during chronic opiate abuse to behave differently than a non-dependent individuals.

Nor do I see how 'just' having too many receptors to fill would cause WD. If an excess of unoccupied receptors caused WD, then anyone would go into WD anytime they took naltrexone.

But of course WD is NOT caused by not having enough receptors to fill, that doesn't make sense, if it were anything so simple it would be more like not having enough peptides to fill those receptors. But I don't think receptor density is the primary player at all.

I think WD is too complicated to be understood with one explanation. I think there are a combination of factors at work. If I read more about it I would probably find out I am completely wrong. But I think it has less to do with the number of receptors as to how those receptors, and the systems they are involved in, are wired.

Such as, when a receptor is constantly occupied by morphine, the receptor doesn't internalize, the signal is transduced. What if after signal transduction, when the receptor becomes un-occupied, because of signal transduction the receptor acts as if it were occupied by an inverse agonist. (Kind of like how naltrexone acts like an inverse agonist when it is ripping agonists off receptors that have been compromised by agonist abuse, but if no full agonist are there it is just an antagonist, and naltrexone generally won't easily cause PWD in non-dependent individuals)

And of course your body produces less endogenous opioids and increases production of enzymes which target those endogenous opiates, in response to long term chronic abuse.

Not to mention how other endogenous opioid peptides could be involved(such as dynorphin).

What I am confused over is whether WD is ended by your body producing more endogenous opioids or from receptor up-regulation.(or both?) I would assume acute WD is ended by increased production of endogenous opioids, and PAWS is caused by long term receptor transduction, which takes longer to heal.

I mean, tolerance isn't dependent on receptor density, why should WD be?

 

[alkap555]

As far as I know, the EXACT mechanisms have not been fully elucidated, but are thought to involve alterations in the cAMP secondary messenger cascade of opioid-GPCRs (G-prot coupled receptors). Short term adaptations probably involve beta-arrestin mediated receptor internalization.

With regards to desensitization, in vitro and in vivo data seems to be conflicting. I do know of several studies and review articles that demonstrate chronic mu-opioid agonist administration does NOT result in receptor desensitization. However, there are many studies that indeed show desensitization.

I don't think there is a clear answer to these questions. If I had to guess I would say that dependence and the withdrawal syndrome are due to various mechanisms including receptor desensitization, downregulation, g-protein uncoupling and alterations in the secondary messenger systems leading to adaptations in gene transcription of endogenous opioid peptides and receptor function.

An interesting study by Bohn et al. (2000) demonstrated that B-arrestin KO mice still developed physical dependence but did not develop tolerance (desensitization), suggesting that multiple homeostatic mechanisms are involved. (Bohn LM, Gainetdinov RR, Lin F-T et al. (2000). Nature 408, pp720-723)

 

[alkap555]

As far as I know, the EXACT mechanisms have not been fully elucidated, but are thought to involve alterations in the cAMP secondary messenger cascade of opioid-GPCRs (G-prot coupled receptors). Short term adaptations probably involve beta-arrestin mediated receptor internalization.

With regards to desensitization, in vitro and in vivo data seems to be conflicting. I do know of several studies and review articles that demonstrate chronic mu-opioid agonist administration does NOT result in receptor desensitization. However, there are many studies that indeed show desensitization.

I don't think there is a clear answer to these questions. If I had to guess I would say that dependence and the withdrawal syndrome are due to various mechanisms including receptor desensitization, downregulation, g-protein uncoupling and alterations in the secondary messenger systems leading to adaptations in gene transcription of endogenous opioid peptides and receptor function.

An interesting study by Bohn et al. (2000) demonstrated that B-arrestin KO mice still developed physical dependence but did not develop tolerance (desensitization), suggesting that multiple homeostatic mechanisms are involved. (Bohn LM, Gainetdinov RR, Lin F-T et al. (2000). Nature 408, pp720-723)

I do not think that WD can be explained as simply as saying "not enough receptors for endogenous opioid-peptides to fill." Chronic op administration results in downregulation of endo-peptides AND the receptor/transduction mechanisms associated with them. Overall you have too little endo-opioid transduction which results in WD

 

[Coolwhip]

With regards to desensitization, in vitro and in vivo data seems to be conflicting. I do know of several studies and review articles that demonstrate chronic mu-opioid agonist administration does NOT result in receptor desensitization. However, there are many studies that indeed show desensitization.

From what I have seen this is largely dependent on the agonist used, whether tolerance builds from beta-arrestin internalization or PKA/PKC-mediated transduction pathways. The mGlu receptors(1 and 5 iirc) have also been implicated in tolerance and WD. But I don't think mGlu antagonists(or at least the ones we have now) are anything anyone should be taking on a regular basis for no good reason.(avoiding tolerance doesn't qualify, too chronic)

 

[sekio]

Sekio's explanation/hypothesis (which is it sekio? Are you just speculating?)

It's just speculation, but it seems to fit all of the needed characteristics of a model for addiction and withdrawal, so that's what I use.

It really would not suprise me if there are multiple homeostatic mechanisms at work here.

 

[alkap555]

Yea, the glutamatergic system is def implicated in plasticity/tolerance, especially amphetamine tolerance. I know a few ppl who have taken low dose memantine (Namenda) and even DXM (disgusting) in conjunction with daily dexedrine et al. to prevent tolerance...who knows if it works. I agree you shouldn't be messing around with NMDA antagonists for no good reason.

 

[arthunter888]

"Opiod tolerance" (illustration video)

This video is largely responsible for my 'understanding' (or lack) of withdrawal. The video states that a rise in opioid tolerance is due to the ratio of opioid receptor recycling vs. receptor degradation being unbalanced in favor of down-regulation.

So when you get high on opiates, your receptors loose sensitivity AND decrease in number in order to mitigate the effects of said external opiates (down-regulation).

Now this is the tricky part. The video is about tolerance, not withdrawal. However, aren't tolerance and withdrawal closely related? For example, an opiate naiive person will require a very low dose of opiates to get high (low tolerance). And also, an opiate-naiive person will NOT experience withdrawal. Conversely, a non-naiive opiate user who has developed a high tolerance WILL experience withdrawal, and the higher the tolerance gets, the more intense the withdrawal becomes.

So, that withdrawal only starts to happen as tolerance rises, and that the WD intensity increases as tolerance does, would imply a direct relationship between them, right? This is what leads me to believe that the down-regulation of receptors (tolerance rise) is what gives way to withdrawal, because even after external opiates have left the body, the receptors are still too down-regulated to experience the full/normal level of agonism provided by endogenous opiods.

That was my thought process on the simplified explanation of WD (and I'm sure it's faulted as some have pointed out).