a question about opioid antagonists

[thursday]

this is probably going to sound really dumb, but out of curiosity i'm going to ask it anyways. please bear in mind that i don't have any kind of formal education in chemistry, biology, or pharmacology. and i only have very rudimentary knowledge about how opiates work.

that said, i've read that exogenous opioids work by acting on various neural receptors which are also activated by endogenous opioids produced naturally by the brain. opioid antagonists on the other hand block these receptors and thus lower the production and availability of opioid hormones which cause the effects experienced by consuming exogenous opioids.

now, if these endogenous opioids and their respective receptors exist in our brain naturally, then that probably means that our bodies naturally produce a certain level of opioid hormones albeit in very subtle amounts. now, when someone takes exogenous opiates regularly then their tolerance goes up, and so for the same amount of stimulation on our opioid receptors, less effects are felt. but what if one took an opioid antagonist regularly for an extended period of time. could a counter-tolerance be developed? could your body adjust to having a constant level of opioid antagonists blocking the receptors so that when you stop taking them your body would actually be more sensitive to both endogenous and exogenous opioid and release more opioid hormones naturally, and thus improve one's general mood without the use of any drugs?

is there anything, and i'm sure there are, which i'm leaving out that would not allow such a possibility?

 

[BilZ0r]

opioid antagonists on the other hand block these receptors and thus lower the production and availability of opioid hormones which cause the effects experienced by consuming exogenous opioids.

Not quite, the antagonists block the receptors, which could potentially (but probably not) increase the amount of endogenous opioids.. but stops exogenous opioids from binding to and activating opioid receptors.

Meanwhile, in response to your main question, the answer is yes/no/maybe...

In a hypothetical receptor system, an antagonist COULD work to increase the amount of receptors expressed, or the efficacy... but they could also cause downregulation too. The thing is that antagonists cause also cause conformation changes in receptors thats encourage them to be downregulated... It's also possible that under normal conditions, there is no steady-state downregulation, so doing things which stop downregulation aren't going to effect anything, because there is no downregulation to stop. There's also the possibility that the endogenous ligand of this hypotherical receptor system is released in normal circumstanses, at such low levels that you wouldn't notice any effect, even if you did get more receptors...

SO! Lets look at the specifics shall we? Well Yoburn et al., 1995 implanted mice Subcuntaneously with a 15-mg naltrexone or placebo pellet for 8 days, and found that the naltrexone increased the analgesic potency of methadone, etorphine, fentanyl, meperidine, and oxycodone by 1.9-3.2-fold... i.e. sensitivity to exogenous opioids went up. He also showed that naltrexone increased the Bmax (total number of receptors) of mu, delta, and kappa opioid receptors by 86, 43, and 33%, respectively. So the amount of Mu receptor went up by 86%.

Now Trujillo et al., 1995 showed that in animals treated with naltrexone showed no alteration in the amount of endogenous opioids dynorphin, enkephalin (enkephaline being a big Mu opioid receptor agonist). So you're amount of endogenous opioids might not change..

So if you're receptors go down, and your endgenous opioids stay the same, then you might think that your general feeling of opioidness might go up...
...BUT there are no studies looking at the time dependence of this effect, it takes just 10-30 minutes of receptors to downregulate in vitro... so I think it's highly likely that as the antagonist washes out of your brain, the downregulation will happen at a similar rate, so you'll never be able to enjoy the high opioid receptor count that you produced.

 

[who mE?]

You may find research on "Ultra Low Dose Naltrexone" interesting.

Unfortunately, the primary self-experimenter on this subject, Mike Strates has apparently taken down his webpage on the subject, www.dilaudid.net ... fortunately, Archive.org DID capture 1 archive of the site before it was taken down, visible here:
http://web.archive.org/web/20040209193610/http://dilaudid.net/uldntx.shtml

 

[ebola?]

Here's a...well...relatively naive question:
Do opiate niave subjects find opiate antagonists taken in high doses dysphoric?

ebola

 

[BilZ0r]

No, usually not.

 

[fastandbulbous]

I thought that the psychomimetic properties of antagonists were generally experienced as being dysphoric, even in opiate naive subjects?

 

[thursday]

wow, thanks BilZ0r. Your post is very informative as usual.

who mE?: i checked out that link you posted and it looks pretty viable for opioid dependent users like myself. i guess from the research that BilZ0r has cited, it's not possible to achieve what i was hoping for, but the results from Ultra Low Dose Naltrexone are quite intriguing and could prove to be worth the hassle of obtaining some naltrex for personal use.

currently i'm on about 400mcg of buprenorphine and about 100mcg of naloxone a day. i've been on the same regiment for about 4 months now so i guess i could have already been experiencing the benefits from ULDNTX from the naloxone since naloxone and naltrexone are rather similar.

 

[thursday]

I thought that the psychomimetic properties of antagonists were generally experienced as being dysphoric, even in opiate naive subjects?

yea i would have thought so as well. i don't quite understand how opioid antagonists can block exogenous opioids while not affecting endogenous opioids. don't the two act on the same set of receptors?

 

[thursday]

k, i did a little more research and i found an article on erowid that talks about orphanin FQ which is supposed to be naturally produced by your body and blocks a lot of the effects of other opioids like morphine. the article also states that chronic opiate users develop higher levels of OFQ which is suspected as a possible cause of physical dependence. would taking OFQ for a long period of time cause a downregulation in your body's natural opioid blocking effects, thus achieving a higher level of opioid-ness once u stop taking it, or would it basically do the same thing as taking something like naloxone?

 

[who mE?]

Do opiate niave subjects find opiate antagonists taken in high doses dysphoric?

While opioid antagonists do not throw opioid naive individuals into withdrawal, they range from not-noticably dysphoric (the person may experience anhedonia too mild to notice), to intensely dysphoric (especially in people with previous opioid or ethanol habits, although they wouldn't strictly count as "naive"). This explains Bilz0r's answer of "USUALLY not"...

I would advise you to look in the direction of these google searches:
http://www.google.com/search?hl=en&lr=&q=naltrexone+dysphoria
http://www.google.com/search?hl=en&lr=&q=naltrexone+mutilation
http://www.google.com/search?hl=en&lr=&q=naltrexone+mutilation+dysphoria

This abstract is particularly relevant: http://opioids.com/naltrexone/dysphoria.html
The patient who experienced "abstinence-like symptoms" [sic: syndrome] highlights a commonly reported phenomenon, where naltrexone can induce withdrawal symptoms even in [a few] patients who have been abstenant for a long time... of course it could just be that the patient was using an opioid not tested for in the screening, but 2 factors speak against this: #1 if an opioid user is smart enough to obtain/use an undetectable opioid, they should be smart enough to avoid naltrexone like the plague (unless "free will" is not a factor), #2: Anecdotal reports on detox related messageboards such as heroin-detox.com or www.atwatchdog.org about people who suffered naltrexone-induced withdrawal after weeks without opioids, and even worse stories of people with naltrexone implants suffering month-long withdrawal syndromes (read some first-hand UROD stories - they're a mixed bag).

and also search for a thread in bluelight (probably in OD) about "runner's high" and endorphins... somebody posted figures from a study involving the administration of antagonists to people before or immediately after (I forget) excersize.

 

[ayjay]

Yoburn et al., 1995 implanted mice Subcuntaneously with a 15-mg naltrexone or placebo pellet for 8 days,

subCUNTaneously?? I'd like to see that......

Seriously though - the dysphoric effects of naltrexone etc are a big worry. I can't believe how gung ho some twits are about naltrexone implants, as if it's some kind of magic button cure for "drargs". Imagine trying to get decent pain relief (say - after a car accident) with a naltrexone implant

 

[BilZ0r]

I should have been more accurate, in general, naive users taking naltrexone don't suffer dysphoria... just like how people on cannabinoid antagonists don't suffer disphoria... This is because the tonic release of opioids in the brain is very very small in comparison to the amount evoked by pain..

Judging from the link posted by who me, opioid antagonists can cause a sort of reverse tolerance... my geuss was just an educated geuss, it must be that opioid receptors regulate very slowly, or more likely, the subsequent molecular targets and circuts must change slowly, and play an important role

The runners figure was by me, the image is this

A: The kind of research which initially was claimed to show that runners high is caused by beta-endorphin, they used antibodies to look for beta-endorphin, but in B: Actual endorphin is measured using a dual antibody method, which shows that most people don't show an increase in plasma endorphin and that the increase is much smaller

There is some evidence that runners high is slightly decreased in people treated with naltrexone/naloxone/naloxazine but those studies are all very weak.