The Big and Bangin' Pseudo-Advanced Drug Chemistry, Pharmacology and More Thread, V.2

[pharmakos]

 

[neurotic]

does 5HT1A agonism play a reasonable role in MDMA's empathogenic effects?
(...)

apparently not: No evidence that MDMA-induced enhancement of emotional empathy is related to peripheral oxytocin levels or 5-HT1a receptor activation

 

[endotropic]

^ that study has some serious problems. For one Pindolol acts as a 5-HT1A partial agonist, not an antagonist, so it doesn't make much sense to reverse a 5-HT1A mediated effect with that drug.

 

[InterestingFACT]

^ that study has some serious problems. For one Pindolol acts as a 5-HT1A partial agonist, not an antagonist, so it doesn't make much sense to reverse a 5-HT1A mediated effect with that drug.

A weak partial agonist would still displace MDMA off 5ht1a receptors. If it has less intrinsic activity than MDMA at the site, a difference in response should be measurable.

 

[neurotic]

^ yes that was the reasoning they presented in the study for using the Pindolol. Wiki also lists it as "a 5-HT1A receptor weak partial agonist / antagonist (Ki=33nM). Alprenolol would be ideal since it is in fact a 5-HT1A antagonist, but, well...

 

[endotropic]

A weak partial agonist would still displace MDMA off 5ht1a receptors. If it has less intrinsic activity than MDMA at the site, a difference in response should be measurable.

Yes it would displace MDMA, but if the empathy response has a low efficacy requirement then a partial agonist wouldn't block the response. Their conclusions might be correct, I just don't find that study particularly convincing.

 

[serotonin2A]

^ that study has some serious problems. For one Pindolol acts as a 5-HT1A partial agonist, not an antagonist, so it doesn't make much sense to reverse a 5-HT1A mediated effect with that drug.

Pindolol acts as an antagonist at postsynaptic 5-HT1A receptors. Despite the fact that pindolol may be a partial agonist at presynaptic receptors, it doesn't make a lot of sense that MDMA would be working through presynaptic 5-HT1A receptors. The only function of presynaptic 5-HT1A receptors is to inhibit the firing of serotonergic neurons, so any effect that MDMA has on presynaptic 5-HT1A would be completely washed out by the huge efflux of serotonin produced by MDMA, which is impulse-independent.

 

[Mr.M.301]

Forgive me if this has already been asked, as I haven't read the entire thread, but I have a question about our current understanding of opioid tolerance and withdrawal.

As I understand it (albeit a very limited understanding), tolerance is caused by downregulation of opioid receptors in the brain. In order to feel 'good' or even 'normal', our brains produce a certain small amount of endogenous opioids (endorphins), and this small amount activates a small number of receptors in the brain (not enough to cause any (down or up)regulation on any discernable scale). When exogenous opioids are taken (say one was to inject heroin), the receptors are flooded with heroin (acting as a ligand (correct me if this term is wrong)), causing a kind of cascading action that produces what we all know and love (the high), and consequently the brain adapts by downregulating (essentially eliminating? or 'deadening'?) the (mu) opioid receptors.

My best attempt at an analogy is that the brain's opioid receptors can be thought of as a bundle of fiber-optic threads. Normally a small little light shines (endogenous production) that keeps us feeling okay. When we take a shot of heroin, it is like pointing a huge floodlight at the strands, and this causes our brain to adapt by removing or disabling many of the strands, and by shutting off the little light (endogenous production). After a while, when heroin use is stopped, the light is off or very dim, and the number of fiber-optic strands are so few that almost no light is getting through, thus we experience withdrawal, until the brain adapts by upregulating (adding / enabling more fibers) and increasing the little light output to previous levels so that we feel normal again.


My problem with this is that I don't see how it explains certain empirical observations, such as the fact that administering an opioid antagonist (naloxone or naltrexone) to opioid naive individuals seems to have no effect. If the above model were correct, wouldn't the antagonist block the effect of endogenous opioids, thus causing dysphoria or even symptoms similar to mild precipitated withdrawal?

Is there any other theory of tolerance and dependence that has any sort of traction? From my own naive perspective, it would seem to make as much sense that the body produces its own endogenous opioid antagonists, in proportion to how much activity is detected at the receptors. In addition to explaining tolerance (the more activity at the receptors, the more antagonist production occurs, thus lowering the number of available receptors open to exogenous opioids, i.e. heroin, and necessitating an increase in dose for the same effect), as well as withdrawal (when the exogenous opioids are ceased, the receptors are blocked by the endogenous antagonist produced, thus causing withdrawal effects until the antagonist is metabolized and production is ramped back down). I don't pretend to think this is correct, but I'm wondering if this has been explored and rejected, and if so what the explanation is, or if there is a possibility that this mechanism or something similar to it is even realistic.

Thanks.

 

[sekio]

the fact that administering an opioid antagonist (naloxone or naltrexone) to opioid naive individuals seems to have no effect.

That's untrue. If you give a sober person a shot of naloxone they'll almost assuredly feel like crap.

wouldn't the antagonist block the effect of endogenous opioids, thus causing dysphoria or even symptoms similar to mild precipitated withdrawal?

They do.

Something to consider is that morphine and 6-acetylmorphine are synthesized in mammals, including humans. So opioid usage may actually be disrupting a natural equilibrium in a pretty obvious way.

it would seem to make as much sense that the body produces its own endogenous opioid antagonists, in proportion to how much activity is detected at the receptors.

If cells were secreted opioid antagonists people would be able to collect those compounds and test them on control cells.

 

[pharmakos]

That's untrue. If you give a sober person a shot of naloxone they'll almost assuredly feel like crap.

i've had arguments about this with several people, both "IRL" and online. some day i am going to take a naloxone shot while sober as a way to try to prove that opioid antagonists are indeed dysphoriants. i suppose proving that i am not just experiencing the placebo effect with be difficult.

and re: endogenous opioid antagonists... i think if the body knew how to produce opioid antagonists, it would have by now evolved a mechanism for mass-producing them as an antidote to accidental opioid overdose. but, considering how deadly opioid overdoses are, i doubt humans have any sort of a mechanism for producing opioid antagonists. though the possibility that we just haven't made that evolutionary leap yet remains.

 

[neurotic]

^ that dude from Vice tried that already didn't he

 

[endotropic]

My best attempt at an analogy is that the brain's opioid receptors can be thought of as a bundle of fiber-optic threads. Normally a small little light shines (endogenous production) that keeps us feeling okay. When we take a shot of heroin, it is like pointing a huge floodlight at the strands, and this causes our brain to adapt by removing or disabling many of the strands, and by shutting off the little light (endogenous production). After a while, when heroin use is stopped, the light is off or very dim, and the number of fiber-optic strands are so few that almost no light is getting through, thus we experience withdrawal, until the brain adapts by upregulating (adding / enabling more fibers) and increasing the little light output to previous levels so that we feel normal again.

It might be more useful to imagine endogenous opioids as a faint light that only blinks occasionally rather than a constant "small little light". Most of the time there is hardly any endogenous opioids in the synapse available to act on the opioid receptors, but certain situations (sex, excessive exercise, certain types of pain, etc.) can cause a release.

Taking an opioid antagonist might have a disruptive effect on how you feel in those types of situations without having a noticeable effect most of the time.

 

[neurotic]

Not much happens in the opioid receptor system in regular conditions then? Like it doesnt work constantly like say serotonin or dopamine?

 

[sekio]

I suspect endogenous opioid release is required for proper functioning of e.g. reward and pain regulation circuitry. It's probably more active than you'd expect.

 

[nAON]

^ innit. Otherwise pinning sober people up with naloxone wouldn't have any effect until you get yer cock out. Hell there's even a bit of flipflop there when you mentioned serotonin, and I immediately thought about the subtle effects of SSRIs that become most evident when you're trying to have an orgasm.

 

[InfectedWithDrugs]

Maybe I should have posted this - http://www.bluelight.org/vb/threads/765123-Need-to-understand-buprenorphine-better here..? It seems like nobody knows much about buprenorphine, but I only made that thread yesterday...

 

[Mr.M.301]

I wanted to note two other phenomena in which my understanding of the opioid system doesn't seem to explain:

-I have noticed that after I had been using opioids for quite a while and had become heavily dependent as well as tolerant to them, that the effects of the 'high' and the withdrawal effects started to overlap. This was most noticeable with short half-life full-agonists (e.g. heroin); I would start noticing the beginning of withdrawal symptoms before the intoxicating effects had completely worn off (my pupils would still be pinned, I would still feel slightly euphoric, the analgesic effect would still be there, but I would start yawning, tearing up, have that 'throat gurgling', etc, indicative of the onset of withdrawal).

-I have also noticed (I'll try to describe this as professionally as possible but it's inherently a little gross) that when on the toilet (while defecating), I would notice by body was experiencing symptoms identical to worsening withdrawal (pupils dilating, chills/sweats, goosebumps, runny nose, tearing, etc) while defecating. This was pretty rapid and fairly drastic, and would subsequently reverse effects (presumably due to endorphin release) when I was done. I would get up and wash my hands, notice my pupils were slightly pinned, feel the typical endorphin effects for at least a few minutes afterwards. The latter effect seems to clearly be related to endorphin release, but what about the former effect?

Clearly the gi-tract is heavily influenced by opioids; is it possible that the brain uses them somehow as a signalling mechanism to induce defecation, by temporarily increasing gut motility and muscle contractions, or something like that? I was reading the following but I'm having a little bit of a hard time understanding exactly what it is saying with regards to this issue specifically:

The release of opioid peptides from enteric neurons can be accompanied by substantial changes in motility and secretion (8, 43). The inhibitory effect of opioid agonists is related to interruption of neurotransmission within the enteric nerve pathways governing gut muscle activity (8, 46, 47, 48). Opioid receptor agonists can interrupt both excitatory and inhibitory neural inputs to the musculature of the gastrointestinal tract; inhibition of excitatory pathways inhibits the release of excitatory neurotransmitters, such as acetylcholine, and blocks distension-induced peristaltic contractions (Figure 2). In contrast, blockade of inhibitory neurotransmission results in suppression of nitric oxide release from inhibitory motor neurons, disinhibition of gastrointestinal muscle activity, elevation of resting muscle tone, as well as nonpropulsive motility (7, 8). Because opioid receptor agonists can influence both excitatory and inhibitory activity, as well as activate the interstitial cell–muscle network, their effects on gastrointestinal motility and secretion can be complex. μ-Opioid receptor agonists inhibit gastric emptying, increase pyloric muscle tone, induce pyloric and duodenojejunal phasic pressure activity, disturb the migrating motor complex, delay transit through the small and large intestine, and elevate resting and sphincter pressure (8). In addition, the μ-opioid receptor agonists inhibit gastrointestinal ion and fluid transport (Figure 2). As a result of the combination of prolonged contact of the intestinal contents with the mucosa and interruption of prosecretory enteric reflexes, opioids attenuate the secretion of electrolytes and water and facilitate the net absorption of fluid (8).

The effects of μ-opioid receptor agonists on the gut are mediated by interaction with enteric μ-opioid receptors. The transduction of a signal through these receptors can result in activation of a number of pathways, including activation of potassium channels, membrane hyperpolarization, inhibition of calcium channels, and reduced production of cyclic adenosine monophosphate (8). All three classes of opioid receptors—δ, κ, and μ—have been shown to contribute to opioid-induced inhibition of muscle activity in isolated human intestinal tissues (5).

 

[IndustrialStrength]

^ I don't have much to contribute in terms of an answer to your question;
but would like to anecdotally add that I also have experienced these same effects.
Though I would like to add that the effects don't necessarily reverse themselves.
Also the effects as he stated are quite drastic, sweats, tearing, pain, etc.
Often I take medication on the way to the bathroom to counteract the after effects.
IE. Oral Methadone or Oxycodone (What I'm currently prescribed) so that upon completion
of the aforementioned movement I don't enter withdrawals.
As such I would also be interested in anyone's take on this particular question.
Thanks to anyone who has any input on said questions of the above poster.

 

[Oxide]

http://www.sciencemag.org/content/349/6249/677.full

neat discovery.

 

[IndustrialStrength]

@Oxide neat discovery indeed, thanks for sharing.

Has anyone found or know of any references to what Mr.M.301 was referring to?
If so I'd be very interested in reading them, so please post or PM me any that anyone happens to find.

On a similar note I have noticed that eating tends to bring on opiate withdrawal symptoms in my case.
I've been searching for any journal articles or references to this phenomena but to little avail.
If anyone has any links to articles or other information regarding the stated phenomena please post or PM.
Thanks to whoever may post or PM said information.
And as always thanks to those who contribute to the knowledge base available here.
It's greatly appreciated even by those who usually prefer to lurk more than post here. Thank you.