Is the upregulation of opiate receptors permanent???

[tayo]

so as seen in opiate use over time...
downregulation of endogenous opiates and upregulation of opiate receptors.

but a question...
so wait now if this is true... after withdrawals what has happened, does the body keep the same number of receptors it has upregulated and maintain a new upregulated pain response system? or does it downregulate to return to previous levels prior to opiate usage? because if it maintained a pain response system, would make any future opiate use more succeptible to worse withdrawals and potentially more addiciton right?... for life... like.... do the upregulated opiate receptors die?.. or are we stuck with extras from exogenous use?

this could go for many drugs.

can anyone offer evidence or personal experience or of others that would back one up what happens?

any thoughts?

[Orchid_Suspiria]

Swim is obviously not a doctor by any means but he can tell you how he feels.Even months after physical withdrawal he does not feel right,little aches and pains that wouldn't bother most people can drive swim insane.Swim does not think he will ever feel "right"again,atleast not without opiates.Swim hopes his personal experiences helps in determining an answer

[lulz]

Anecdotal evidence aside, it might be useful to consider SSRI drugs.

The accepted explanation for how SSRI drugs work, particularly taking into account the 4 week plus period before they improve anything, is because they agonise autoreceptors (receptors which perform the opposite function as receptors, they shut the neuron down, much like a thermostat). In this line of reasoning, a patient takes an SSRI long enough for his serotonin neurons to become habituated to a high level of serotonin activity, and when they stop taking the SSRI the neurons behave as if the same level of autoreceptor activity is going on even though it isn't (resulting in a net increase in neural activity along serotonin neurons).

I suspect that if asked, a conventional neurologist would say that neurons adapt to increased levels of activity, but if activity drops the neurons stay accustomed to the previous high level of activity. There is a metaphor I am trying to think the name of, you know those gears that can only turn in one direction? Like on old tennis nets? Hmm... Well that's the kind of behaviour I'm talking about. Neurons can be geared up, but they don't seem to be very good at gearing down.

Bearing in mind that for the VAST majority of human evolution, we were not regularly exposed to chemicals that manipulated neural activity, this would make sense.

Reputation Comments on this post:

good input

[MrJim]

The receptor sites do close during and after withdrawals. Your brain essentially goes back to the same number of sites as before the addicition. It does take a little time though. Which is one of the contributing factors to the depression onegets in and just after withdrawal. The sites are still healing.

[stoneinfocus]

I wouldn´t generalize the adaption of receptors to overstimulation and autoreceptor activity -it´s too complex and there´re too many different mecahnisms in regulating feedback / inhibition also in the different varities of receptors and endorine drug secretion.

Let alone the feeling "hunger" is regulated by so many cytocines that one will never experience the same hunger in his live two times.

And activation of endocrine action is easily and succesfully achieved by inhibition of certain receptors and antagonising drugs. Then again, you´re right on the point that everything that persists for a long time manipualting the body´s chemistry, it might have a serious impact on the endocrine system, like 2 months of heavy corticosteroid-use will stop endogenous production for longer than a year, which is an ubearable situation.

While the fear of systemic corticosteroisd use is not justified in most cases, use of +30mg/day prednisone eq. over more than a good month is something to worry about or at best be avoided.

there seems to be somehow a magic in 4-12 weeks as a "long time" for a drug use to kick in and/or develop unfaverable sides.

[MrJim]

A little lost here co-incidence. Not really following you here. Things are complex, yes. But I simplified a situation for better understanding. It is the same thing I learned in my Neuropsychology courses.

[darawk]

Opioid antagonists can increase receptor density/sensitivity in the same way that opoiods decrease it. They've also found that very low doses of naloxone co-administered with opioids almost completely reverses tolerance, even in heavily tolerant subjects. NMDA-antagonists(dxm/ketamine) are pretty good at this as well.

[tayo]

does anyone have a study to back this up by any chance?

[stoneinfocus]

Originally Posted by darawk

Opioid antagonists can increase receptor density/sensitivity in the same way that opoiods decrease it. They've also found that very low doses of naloxone co-administered with opioids almost completely reverses tolerance, even in heavily tolerant subjects. NMDA-antagonists(dxm/ketamine) are pretty good at this as well.

to Mr, Jim -that was what I was trying to link with these analogies, but I yet don´t know much about opioid receptors and regulation / rns-expression and antagonizing drugs...

I came from the Hypothlamic - pituitary - gonadal - adrenal axis and worked my way through from glucose-tolerance ,HSP, to catecholamines, and all the agonists and antagonsits, feedback inhibitors, secretolytica, but unfortunately not opioid receptors.

[Laudaphun]

Originally Posted by darawk

Opioid antagonists can increase receptor density/sensitivity in the same way that opoiods decrease it. They've also found that very low doses of naloxone co-administered with opioids almost completely reverses tolerance, even in heavily tolerant subjects. NMDA-antagonists(dxm/ketamine) are pretty good at this as well.

So are you saying that suboxone (buprenorphine/naloxone) would cause reversal of ones tolerance? Or that in this case it would not because the naloxone has such low bioavailability?

[lulz]

I've also read the same thing about opioid antagonists, the idea was that they should be taken at extremely low doses (either 1/25 or 1/50 of the regular dose), and just as importantly the dose should be taken at night.

As I recall the explanation had something to do with the fact that the brain regulates homeostasis mostly during sleep, and a tiny dose of the antagonist will trick the brain into thinking that production of the neurotransmitter in question is too low, therefore it would boost production of that neurotransmitter.

The thing I read was also written by a former addict, who said that this had proven far more effective than methadone treatment for him. I also read something written by somebody about using a beta-blocker in the same way to treat anxiety, although the mechanism behind this seems counterintuitive.

[tayo]

so we are saying that the receptors "swell up" basically and shrink, and are ruling out that they increase and decrease in number? ..or simply increase in number and endogenous opiates increase in number as well?

[MrJim]

No, Extra gates are created, upregulation. That is why it is impossible to to the same amount day after day and get the same level of high.

[tayo]

right, so if someone were to take naloxone or other antagonists for a period of time, the system would downregulate receptor activity? and tolerance would decrease immensely to opiates? so it works both ways. but science doesn't have proof of how exactly it works? is there a conclusion swim missed to the original thread question?

[MrJim]

If I can dig up my text books I'll look into it. Typically in the neuroscience courses, unless something was conclusively proven, it tended not to be taught. It is the only real science subsection of Psychology.

[toe]

I don't know about reversal, but there seems to be evidence that simultaneous use of an agonist w/ an antagonist can prevent tolerance from developiing in the first place. There are a couple of new drugs in the pipeline (because in Amerikkka big pharma will never sell you two pills when they can get a shiny new 20 year patent selling you one) I don't remember all the details, but one of them is called "Oxytrex", and the ingredients should be self-evident.

[Ethyl]

This (antagonist can prevent tolerance) is known for quite some time now, and only now it's being trying to be sold as a pill.

Big pharma loves their opiates proffits, a pill that would not put people addicted to it it's not that profitable when compared to "tradicional" opiates..

[lulz]

Originally Posted by tayo

right, so if someone were to take naloxone or other antagonists for a period of time, the system would downregulate receptor activity?

More than that: the average number of receptors on that type of neuron would increase. Which would make it much easier to activate those neurons.

Neurons "grow" receptors like plants if neural activity is too low, and their receptors die off if activity is too high.

When people who drink a lot talk about developing a "tolerance", what they mean is that the average number of receptors on GABA neurons has decreased. Same sort of thing happens when people become dependent on most drugs.

Reputation Comments on this post:

Good post.

[Ethyl]

One thing to add...

Receptor upregulation of opiate receptors is not the only reason why we feel shitty after stoping regular opiate use. There are natural endorphins that are opiate antagonists and their elevated levels in addicts is the one of the reasons to feel shitty...

Another way to feel shitty is elevated levels of kappa agonists like dynorphin.

EDIT: Like everything in nature...: For every Ying substance there are Yang substance(s) that are produced...

[Caitlin23]

Originally Posted by Orchid_Suspiria

Swim is obviously not a doctor by any means but he can tell you how he feels.Even months after physical withdrawal he does not feel right,little aches and pains that wouldn't bother most people can drive swim insane.Swim does not think he will ever feel "right"again,atleast not without opiates.Swim hopes his personal experiences helps in determining an answer

Swim has found, personally, from past experience, that it takes her 9 mos. to get back to feeling "normal" again, but poor little swim was stupid and as soon as she felt better she picked up the habit again. Don't make that same mistake. Best of luck!

[fiveleggedrat]

As I recall the explanation had something to do with the fact that the brain regulates homeostasis mostly during sleep, and a tiny dose of the antagonist will trick the brain into thinking that production of the neurotransmitter in question is too low, therefore it would boost production of that neurotransmitter.

So then, according to this, if Swim bombarded his brain with antagonists like naloxone while being opiate free and did this for a decent amount of time, would it reverse the effects of a non physical/addiction type tolerance? Swim is an infrequent user, but tolerance has shot up 2x to 3x over time.

Any ideas/thoughts, anyone? Has anyone ever tried this?

[chillinwill]

SWIM hasn't done naloxone but is on naltrexone which is an antogonist and hasn't used opiates in just about 6 months now but when he has relapsed while being on naltrexone, he feels no high (slight initial rush) but that disappates in less than a minute

[fiveleggedrat]

Swim meant dosing with a antagonist for say, 2-3 weeks daily, and then staying clean off that antagonist for say, 1-2 weeks or whatever appropriate half life to get the drug out. Then, after it was all out, dose with an agonist.

fiveleggedrat added 10 Minutes and 26 Seconds later...

After much reading, I believe the answer to mental tolerance is naltrexone treatment while sober. Swim will plan on experimenting with this.

[fiveleggedrat]

As time passes, Swim becomes more and more sure upregulation is permanent, at least for him.

Check out the link in Swim's thread, he's trying to find a way to reverse this permanent upregulation.

[sl1p609]

swim have been hearing allot about Activate Charcoal and taking the excess toxins or filters swim don' t know, Its supposed to expand in your stomach and for how long does swiy do this 1 cap a day..

suggestions, swiys says that its may or may not be a good idea

like puking for 10 hours straight from over dosing lol is this right