Ampakines (and tianeptine) alleviate respiratory depression

[dopamimetic]

... caused by opioids, but also barbiturates. Very interesting and looks somewhat more promising than the unreliable 5-HT based approach.

Ampakines alleviate respiratory depression in rats. (from 2006 and 2009) and
Tianeptine prevents respiratory depression without affecting analgesic effect of opiates in conscious rats. (08/2015)

As I can't access the full texts, I don't know if they say anything about the dosages used and the potency of this effect.
So might tianeptine actually be the first 'safe' opioid at least in that it won't kill one by oxygen depletion?

And at least one of the AMPAkines used in the studies, CX-546, looks strikingly similar to the easily available sunifiram:

How comparable are sunifiram / unifiram to these compounds in terms of potency, etc? Might they be a potential harm-reducing additive when using opioids - even more so with memantine on top of them (or with DAMGO, of course)?

Doing opioids without tolerance and respiratory depression - there must be a catch somewhere.

 

[InterestingFACT]

Tianeptine almost certainly counteracts its own respiratory depression (it's antidepressant effects... and its recreational effects.... are due to full agonism at the mu-opioid receptor). It makes sense given what we know about it--that it causes BDNF release through AMPA modulation--and given the total absence of respiratory depression as a symptom or side effect, across numerous anecdotal reports across the web about people abusing tianeptine in insane dosages.

I've heard/read a few anecdotal reports of people using sunifiram to counteract overdoses on fentanyl analogues with great success. And, this is a much more uncertain proposition, but I also feel like I notice its respiratory-stimulant effects even at regular doses while not attempting to counteract a downer. Of course most any stimulant will tend to increase respiratory rate, but it's something I specifically noticed on sunifiram. I expect it would do the job quite well.

Now, there's the question of whether this is something that should be done. In addition to its effect to counteract respiratory depression, sunifiram is a powerful nootropic that acts on the glycine binding site of NMDA receptors, increasing CAMKII and PKCa phosphorylation. This causes a PKCa-mediated increase in NMDA signalling, and a PKCa and CAMKII-mediated increase in AMPA signaling. This, in turn, causes a dose-dependent increase in NMDA-mediated and AMPA-mediated LTP.

In short, it's rewiring your brain. Which is pretty cool. But less cool if you mostly take it while abusing opiates. In that case, its theoretical positives--learning, integrating, and reinforcing positive habits--turn into a very serious negative: reinforcing your addictive behaviors. These kinds of powerful LTP enhancers coming to the nootropics/RC market are powerful and potentially wonderful with careful use... but they're used most appropriately when taken only on the "hard days," when you know you have a ton of work to do, and won't be messing around playing videogames, doing drugs, browsing reddit or bluelight, etc.

Beyond that, I don't particularly like the idea of sunifiram, or other AMPA-mediated respiratory stimulants, becoming part of some "common knowledge combo" to allow doses to escalate past the "natural" lethal dose. People die all the time as it is, just trying to shoot below their OD point, due to sheer stupidity, or to changes in setting and ritual, or just carelessness. Now imagine a world where people can start purposely taking doses that should kill them, by throwing a little sunifiram into the shot? Now there's a lot more room for mistakes, and a lot more room for people to end up dead.

Naloxone is a must-have for anyone with an opiate habit and a reckless streak. It will save your life. But the fact that it comes at a cost--that it kills the high and precipitates withdrawal--that moderates its usage.

It's very common in a hospital setting, especially when it comes to the elderly, that can only provide partial or insufficient analgesia, due to safety concerns. In such a setting, the introduction of AMPA modulators as a new therapeutic class to enable better care of the elderly, opioid-tolerant, or seriously injured would be a wonderful idea. And I'm all for anything that could save lives. But I think such a "combo" is likely to inspire many horror stories of its own. It's probably best that people stick with naloxone for the life-threatening cases, and just take the rest as it comes.

 

[serotonin2A]

Tianeptine almost certainly counteracts its own respiratory depression (it's antidepressant effects... and its recreational effects.... are due to full agonism at the mu-opioid receptor). It makes sense given what we know about it--that it causes BDNF release through AMPA modulation--and given the total absence of respiratory depression as a symptom or side effect, across numerous anecdotal reports across the web about people abusing tianeptine in insane dosages.

Why do you think that tianeptine "counteracts" its respiratory depression, as opposed to just not having a strong effect on respiration? There are plenty of opioids that do not produce significant respiratory depression. For example, partial agonists like buprenorphine. Agonists that are selective for mu-1 (a MOR subtype produced by post-transcriptional modification) are also believed to produce relatively little respiratory depression.

So little is known about the opioid activity of tianeptine that it is premature to view it as a full agonist that should produce respiratory depression. The effects it produces on opioid receptors would appear to be moderate, at best, based on reports from people who have taken high doses.

 

[InterestingFACT]

Why do you think that tianeptine "counteracts" its respiratory depression, as opposed to just not having a strong effect on respiration? There are plenty of opioids that do not produce significant respiratory depression. For example, partial agonists like buprenorphine. Agonists that are selective for mu-1 (a MOR subtype produced by post-transcriptional modification) are also believed to produce relatively little respiratory depression.

So little is known about the opioid activity of tianeptine that it is premature to view it as a full agonist that should produce respiratory depression. The effects it produces on opioid receptors would appear to be moderate, at best, based on reports from people who have taken high doses.

You're right, perhaps that's premature. However, given that the study he linked above demonstrates that tianeptine also prevents respiratory depression induced by morphine, it seems fairly logical to put Occam's Razor to work here and assume that this effect would minimize any respiratory depression from tianeptine, and therefore it's impossible to conclude its selectivity for mu subtypes.

However, this article does provide some interesting insight:
http://jpp.krakow.pl/journal/archive/03_02/articles/09_article.html

Particularly this section:

The effect of an acute and repeated treatment with TIA or FLU on the levels of Met-Enk in the studied tissues and plasma of the rat are summarized in Table 1 .

Single administration of TIA resulted in an increase in the level of Met-Enk in pituitary gland (both intermediate and anterior lobes),while in the hypothalamus, adrenals,plasma and striatum,the decrease in the level of Met-Enk was observed.In addition,single administration of FLU induced the decrease in the level of Met-Enk in the hypothalamus,adrenals,plasma and striatum.

On the other hand,both TIA and FLU,administered repeatedly,decreased the level of Met-Enk in striatum and hypothalamus,but in the hippocampus as well as in the neurointermediate lobe of pituitary,the increase in the level of Met-Enk was observed after repeated administration of both TIA or FLU.

In the anterior lobe of pituitary,adrenal glans and plasma,the effects of repeated administration of TIA or FLU were differentiated,i.e.FLU did not induce any significant changes in the level of Met-Enk,while an increase in the level of this peptide in an anterior lobe of pituitary and adrenals,and a decrease in this parameter in plasma,was observed following repeated administration of TIA.

No significant changes were observed in the level of PENK mRNA following acute or repeated administration of TIA or FLU in the rat brain,pituitary or adrenal glands (Table 2 ).

Now this is comparatively ancient research, and predates all the recent talk about tianeptine having a direct mu or delta opioid affinity, but it differentiates it from fluoxetine (which also changes opioid peptide expression) by its ability to increase Met-enkephalin in the pituary after single administration (though it decreases it in adrenals, like fluoxetine), and after repeated administration in both the pituitary and adrenals. This would imply some interesting selectivity to its effects. The authors would have assumed at the time that this effect, like fluoxetine's, is downstream of some regulation of serotonin (they still characterized it as an SRE).

However, we have research that indicates it's affinity for mu and delta:
http://www.nature.com/tp/journal/v4/n7/full/tp201430a.html
And we've also failed to find any direct binding at monoamine or glutamate receptors. It appears to increase or decrease NMDA EPSPs depending on brain region, and it increases the phosphorylation state of AMPA1, at the CAMKII site Ser831 and at the PKA site Ser845. But as far as I know, no binding event has been found to explain any of this. It doesn't bind receptors or enter transporters.

There's obviously something funny about the stuff--and I'm willing to believe that it might bind selectively to non-respiratory depressive mu sites, but given that its interaction with AMPA is obvious--even if the exact point at which it interacts is still a mystery--and given that AMPAkines are known respiratory stimulants, and finally given that tianeptine is a demonstrated respiratory stimulant, and meanwhile that other selective/partial agonist opioids generally aren't...

Are you suggesting that tianeptine's NMDA/AMPA modulating effects are purely mediated by its activation of specific MOR?
I've read about the extensive cross-talk between opioid and AMPA and NMDA, like here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034717/
And while fascinating, it seems contradictory to the the hypothesis that an opioid agonist could directly cause respiratory stimulation. If some MOR are ultimately stimulating via AMPA cross-talk, but other MOR (and DOR, which are often heterodimerized with mOR) are depressive, then how do you suggest that tianeptine, with its relatively unimpressive binding values, could displace a stronger, less selective, opiate like morphine, which is blanketing receptors?