supposedly a way to experience opioid high without running the risk of addiction

[iskandar]

I figured this would be the sub-forum to post this, sorry if I was wrong

So basically it's something of a commonplace that drugs that act as agonists at certain receptor sites cause a long-term effect of downregulation thereby effecting a rebound tolerance and/or withdrawal (not necessarily though). Same goes with antagonists apart from the fact that the key process is upregulation. Without going too much further into detail that you folks surely know lots better than I do, I just figured that u-opioid agonism, notorious for its huge capacity of creating dependency where it involves taking exogenous agents, can in itself be produced as a rebound effect secondary to an antagonist's action.
u-opioid receptors seem to up and downregulate within hours and days, giving way to heroin withdrawal taking a couple to a few days to subside. I believe a selective u-opioid antagonist (anybody can suggest one? Naloxone is not selective I hear) that would feel to a 'healthy' individual much the way heroin withdrawal feels to an addict might produce the opioid tolerance in reverse, upregulating u-receptors with each dose. Of course that would require much struggling each time due to the drug's supposed profoundly unpleasant effects. However, imagine somebody taking increasing dosages of a u-opioid antagonist over the course of a week then to discontinue it to experience an ongoing opioid high without any agonist whatsoever, entirely due to the upregulated state of one's receptors after the repeated antagonist administration. That strikes me as a valid method, inherently free of any risk of addiction since the CNS never gets to learn the link between a euphoria-inducing substance and the consecutive euphoric state.

I'm longing to know what you people think of this!

 

[enduin]

I think it can't work, but surely people more knowledgeable will give more technical detailes. Also even if it worked, logic tells me that for how much you upregulate your receptors you still have to activate them, that would mean release some endorphins with strenuous gym exercise or self-induced pain. Also this would work in reverse, so you'd need to do that while taking the substance to get the supposed upregulation (your body can't activate the receptors when needed so it upregulates them). So all in all you'd need to suffer WDs, keep harming yourself or getting wasted in the gym before and after to get a high. Not a good deal IMHO.
Again I just used logic.

 

[daddysgone]

This would not work for many reasons.
But first let me say that if someone who is not dependant on opioids were to take an antagonist, they would not suffer withdrawal. Antagonists cause precipitated withdrawal in those who are dependant on opioids because of the extremely rapid removal of relatively high concentrations of agonists, from their receptors. For those that are not dependant on opioids, they would not be "accustomed" to these high concentrations, and withdrawal would not result.

Regarding why your plan would not work:
As someone pointed out, even if you succeeded in upregulating your receptors (I suspect you would to some degree), you would still need an agonist to activate them. Now it is true that you have endogenous opioids, but you must understand that you do not release these endorphins at concentrations even CLOSE to the levels of what would be considered a "recreational dose".

I think that what you are saying is that in THEORY, if you were able to upregulate your receptors to an extreme level, even a modest release of endorphins could create an agonist effect equal to a recreational dose of exogenous opioids. However, in practice I am certain that there is no way to upregulate your receptors to anywhere near this level.-DG

 

[iskandar]

Well, I probably should specify I didn't mean that the rebound euphoria were to go on indefinitely, my point is that immediately after ceasing to redose on the mu antagonist one would go into an opiate-like state that would only last about as long as it ever takes to get your receptor levels back to baseline. I'd guesstimate a day or two but it might have all the span of a heroin withdrawal. Perhaps that depends on the extent to which you have upregulated.
Also you won't have to purposely induce endorphin release. Mostly every neuromodulator system has some baseline activity and that will be properly amplified by elevated receptor levels. Otherwise everybody would be spontaneously plunging into opiate WD's every so often lol :D

P.S. ^And of course I'm not talking about euphoria near as intense as it comes with heroin, but that one is way over the edge anyway. And why wouldn't I get dysphoria and a WD-like state if I were to take a selective mu antagonist to filter out the baseline endorphins?

 

[nodemeritus]

iskandar:

your idea is is the stupidest thing I have ever read on this forum. it's stupid in theory and anyone who would try such a thing would have to be profoundly retarded. you should go smoke a joint and stop trying to thinks so much.

 

[iskandar]

^
ha ha dude... Everyone's brains is wired in their own fashion. Obviously, you're not a thinker if you can't appreciate a good old hypothesis however

 

[nuke]

Take opiates and then decide not to take them again?

 

[iskandar]

^ Rather to get an idea of what mu-opioidergic high is like without ever exposing oneself to highly addictive substances.

 

[daddysgone]

Well, I probably should specify I didn't mean that the rebound euphoria were to go on indefinitely, my point is that immediately after ceasing to redose on the mu antagonist one would go into an opiate-like state that would only last about as long as it ever takes to get your receptor levels back to baseline. I'd guesstimate a day or two but it might have all the span of a heroin withdrawal. Perhaps that depends on the extent to which you have upregulated.
Also you won't have to purposely induce endorphin release. Mostly every neuromodulator system has some baseline activity and that will be properly amplified by elevated receptor levels. Otherwise everybody would be spontaneously plunging into opiate WD's every so often lol :D

P.S. ^And of course I'm not talking about euphoria near as intense as it comes with heroin, but that one is way over the edge anyway. And why wouldn't I get dysphoria and a WD-like state if I were to take a selective mu antagonist to filter out the baseline endorphins?

Again, I understand what you are suggesting in theory, but in practice it does not work out this way (the reason being that the degree to which you will succeed in up-regularing your receptors will not compensate for the lack of a sufficient concentration of opioid agonists on the order of what would be supplied by a "dose" of an exogenous opioid). Do you follow what Im saying?
I think its entirely possible that by doing what you suggest, your mood might be elevated somewhat after your course of an antagonist, due to the up-regulation of receptors. However, this up-regulation will not put you in an "opiate-state" as you put it-there just isn't a high enough concentration of endogenous opioids, even with the up-regulation.

And in response to your question about why wouldn't you experience dysphoria from taking an antagonist if you are not dependant on opioids:
Anecdotal evidence supports that this is not the rule. Many people have taken courses of opioid antagonists (alcoholics for example). It is not typical for these people to experience the type of dysphoria you describe.
Remember that one's "mood" is dependant on many neurotransmitters, not just endorphins. So while an antagonist might block the baseline endorphins of a non opioid dependant individual, this does not have to equte to dysphoria.

However, in an opioid dependant individual, the antagonist will create an immediate shift from high concentrations of opioids (to which the user is accustomed), to below baseline. It is this DRAMATIC shift in opioid dependant individuals that equates to dysphoria. In non dependant individuals, this shift is nowhere near as profound or drastic.

PS- To step away from the science of all this for a second, let me also add:
Even if everything you suggested were to work, wouldn't it be fucking retarded to put yourself through days of what you describe as "dysphoria", just to experience one mild opiate high??-DG

 

[iskandar]

^ I see what you mean. Well, that used to baffle me a lot, too bad it won't seem to work out anymore

 

[Hammilton]

iskandar:

your idea is is the stupidest thing I have ever read on this forum. it's stupid in theory and anyone who would try such a thing would have to be profoundly retarded. you should go smoke a joint and stop trying to thinks so much.

Not even close to the stupidest thing. Miles and miles away.

Nuke's right though.

 

[kken]

desensitization of the micro-opioid receptor is 1 big factor in cause of tolerance build up. Different opioids desentize it differently. agonist only treatment also leads to the g-protein desensitization.

this would explain people's different levels needed to get HIGH (not pain management)
mutations in that gene are common

potent μ-/δ-opioid antagonist basicly stops tolerance in mouse models
μ agonist also tends to make the receptor heteromize with δ receptors (μ-δ receptor) and changing the receptors signaling someways. δ receptor will upregulate and if treatment is continued more of these heterodimers will there be. Hence 10 year ex heroin addict using for 2 days and back to his biggest tolerance he or she had. μ-/δ-opioid antagonist helps decreasing these heterodimers so ex addicts could possibly lower their "permanent" tolerance


cannabinoid system has been linked with slowing the micro-opioid receptor desensitazion and slower desensitazation of the g-protein. cb1 agonist combined with μ agonist can create cb1/μ heterodimers. Not sure how this affects the signaling as i havent followed this area for a while

 

[Hammilton]

1. it's mu, not micro

2. cb1 agonist combined with μ agonist can create cb1/μ heterodimers. Not sure how this affects the signaling as i havent followed this area for a while

obviously, you don't understand how this works. nothing to do with combinging different agonists.

 

[kken]

micro opioid receptor aka mu1 subunit


Concurrent Stimulation of Cannabinoid CB1 and Dopamine D2 Receptors Enhances Heterodimer Formation: A Mechanism for Receptor Cross-Talk?

"Taking the data as a whole in cells expressing both CB1 and D2 receptors, we see CP 55,940 as weakly inhibiting to adenylyl cyclase despite a significant G protein activation occurring as indicated by ERK 1/2 phosphorylation. In contrast, the D2 receptor-mediated inhibition of adenylyl cyclase was significantly more robust than its ERK 1/2 phosphorylation, suggesting that the signaling pathways for these two effectors diverge early. In cells expressing CB1 and D2 receptors, as likely occurs in some neurons, CP 55,940 stimulates ERK 1/2 phosphorylation in part through a pertussis toxin-insensitive pathway. Additionally, in these cells, once adenylyl cyclase activity is maximally inhibited by D2 receptor activation, CB1 receptor stimulation partially reverses the inhibition. Similar concentrations of agonists also increase CB1/D2 receptor dimer formation. Thus, it is reasonable to propose that CP 55,940 signaling through the CB1/D2 dimer activates Gas protein, and that CB1 receptor agonist-induced increases in dimer levels partially reverse D2 receptor-mediated inhibition of adenylyl cyclase."







These results provide the first evidence that morphine regulates the distribution of MORs in neuronal processes, suggesting that "compartment-selective" membrane trafficking represents a previously unanticipated type of opioid receptor regulation contributing to the in vivo effects of opiate drugs on a physiologically relevant population of CNS neurons.
=> improved chances of coexpression?


"Furthermore, a mu-selective
agonist, DAMGO, is also able to increase the number of delta
binding sites as seen in SKNSH cells (Table 1). These results
suggest that mu-selective ligands are able to uncover a hidden
population of delta receptors in cells expressing mu and delta receptors"
"


Cannabinoid Receptor Type 2 Agonists Induce Transcription of the µ-Opioid Receptor Gene in Jurkat T Cells

"CB2 were not changed at the 48-h time point, increased mRNA levels were found not only for interleukin-4 and GATA3, but also
for d-opioid receptors and CB1 receptors (functional proteins were formed)".
=> improved chances of coexpression?


Ligand- and Heterodimer-Directed Signaling of the CB1 Cannabinoid Receptor
", GPCR signaling may be directed toward these selective responses through either strength-of-signal effects resulting from partial agonism or through biased agonism and functional selectivity, resulting from the selective stabilization of one active conformation over the others. This review uses the CB(1) cannabinoid receptor as a specific example to highlight the contribution of two important aspects of GPCR function-orthosteric ligand binding and receptor heterodimerization-toward directed GPCR signaling."



so why not?