Thread: "mu receptors and possible theories of 'permanent tolerance/damage'...."

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    "mu receptors and possible theories of 'permanent tolerance/damage'...." 
    Greenlighter advancedneuropathy's Avatar
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    Jun 2011
    This is not a thread about "my tolernce" and "what's wrong with me". Mods know...just wanted to get that out of the way. That said, myself and others I know have built a permanent 'tolerance' to Opioids. Months with zero exposure and I(we) would still have to take considerably large amounts of whatever was on hand at the time. This has been a factor for nearly two to three years now for myself.

    1. Could it be a Psychological phenomena that occurs, thus causing you to literally stop euphoria subconsciously?

    2. Is it possible that continued use of the P.S. family's milk affectively deteriates/damages the receptors, mainly the nerves, causing dead nerve endings unable to regenerate? Considering neuro-transmitters inform you brain of all things percievable, their damage could put a halt to the party, I would think.

    3. Similar to #2, except more of a combination of exposure and natural cell degeneration. the mu receptors are quick to go with age or are they one of the last things to go? The elderly on their death beds get pumped with Opiate/Opiod medications that seem to be accepted easily. God knows at that point it's probably the best shit you'll have.

    So, has anyone read anything regarding the receptors life cycle and durabilty and is anyone else at that point of what I consider "permanent tolerance"? Is it common or uncommon? I can drink like a fish as well and am currently on a Tram ride that cost me a bit more than the max warning for seizure threshold. I've exceeded many times with no issues. Tram is actually more effective ,proportunately speaking, than most Opes. Just curious about my questions. I just thought to post them in an instant, so forgive me if there is already a thread of this nature(I somewhat doubt that) and that I havn't done enough of my own research on the subject yet. I'll do that now.....Peace. AdNeuro
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    There have been threads on this question suggesting your experience is not unique (also UTSE):

    But I think it is one of those things that can vary from person to person. In the first thread, the suggestion was made that benzo tolerance is permanent. I used to be dependent on alprazolam and took 1-2mg daily. A few years after I stopped, I took some for panic and realized that just .25mg almost put me to sleep. So what's true for some isn't necessarily true for everyone, and there are undoubtedly a huge number of variables. Still, the neuroplastic changes that accompany tolerance are at least somewhat permanent. When I was a kid, if I smoked a cigarette, I would feel dizzy and lightheaded for an hour, and any more nicotine during that time would make me nauseous. I later developed a smoking habit. I haven't smoked or craved a cigarette for years, but I suspect that if I smoked a cigarette today, I'd immediately be back up to a pack a day. The changes that accompany tolerance and addiction remain and can be reactivated.

    Here is a good review of evidence and some speculation about the issue of permanent tolerance in general (not primarily re opiates): Norton S. Is behavior or morphology a more sensitive indicator of central nervous system toxicity? Environ Health Perspect. 1978;26:21–27.

    Here is another study, this time specific to opiates: Mann PE, Bridges RS. Neural and endocrine sensitivities to opioids decline as a function of multiparity in the rat. Brain Research. 1992;580(1–2):241–248. doi:10.1016/0006-8993(92)90950-E.

    The especially relevant part of the article is on p. 245 (keep in mind the study was about pregnant rats):

    The changes in the endogenous opioid system in the present study appear to be associated with a form of tolerance to exogenously administered opiates and opioid peptides that may be permanent. Tolerance may have been produced by the elevated levels of β-endorphin in the brain during the first pregnancy 6 and the repeated exposure of the females to β-endorphin during the first lactation (within the nursing bout) 16. Earlier studies have shown that the number of opioid receptors in the MPOA are higher during pregnancy and decrease during lactation 2°. However, these changes become dampened as a function of multiparity 8. It is also possible that reduced sensitivity to the effect of opioids are 'state-dependent' and are not evident when the females are not lactating. Further studies are planned to examine this possibility.
    I don't think the opiate tolerance is due to neurotoxicity, but rather desensitization and increased autoreceptor & heteroreceptor density. I suspect that your best bet is to either wait longer (you say "months with zero exposure," but perhaps a year or two would be a more realistic timeframe for you), or try a couple weeks of low dose naltrexone (along similar lines as reported here: Webster LR. Oxytrex: an oxycodone and ultra-low-dose naltrexone formulation. Expert Opin Investig Drugs. 2007;16(:1277–1283. doi:10.1517/13543784.16.8.1277)
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    Receptors are proteins and constantly destroyed and recycled. You cannot "damage" receptors.
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    I remember hearing a pet theory once of an immunological/epigenetic change in mu opioid receptors once, can't for the life of me remember where it was but it was one of the papers that lead me to look at epigenetics in amphetamine tolerance. Granted this wasn't a human study and didn't have large effect sizes.

    Euphoria is regulated in a weird, weird manner in the brain so I wouldn't be surprised if your situation had very little to do with opioid receptors.
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    I seem to have a permanent tolerance to the euphoria of opioids and I've never really done them (tried buprenorphin, codeine, opium and heroin.. none produced euphoria).. I have abused amphetamines and MDMA in the past.. possible link?
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    Bluelighter silas GUY's Avatar
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    Nov 2013
    Yeah proteins and enzymes are recycled! However, what about stem cell memory ? are the new MU receptors built with a carbon copy of the first MU receptor you had as a child or is there a adaptation in effect due to environmental consumption ? IDK but tolerance is some special shit man and the human body never ceases to amaze. Biochemistry is like a modulation to our environment, including what our senses at eye level interpret. Who knows what happens at the subatomic level ? i sure dont, i suppose only the atoms know because they are just a little closer in the grand scheme of things !
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    Bluelighter dopamimetic's Avatar
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    Mar 2013
    Chronic use of any biologically active chemical is able to change the genetics (not the best example, but think of antibiotic resistance, or these damn nasty post-SSRI symptoms - I think to remember that for SSRIs it has been proven).
    Last edited by dopamimetic; 06-09-2014 at 18:09.
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    Bluelighter MeDieViL's Avatar
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    Feb 2007
    nmda, antagonists reverse tolerance to pretty much all drugs except gabab, agonists, they work extremely well for opiates, there are different strategy that are like miracle cures in reversing, and bringing back euphoria to all drugs and opiates, I have several projects in mind, the coming months I should come out with more info, either way I did my memantine project years ago, look up Nmda, antagonists for tolerance.
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