Neuroscience The science of cross tolerance in opioids

[Opiophiliclab]

Maybe some of you know that some doctors use a practice known as opioid rotation to prevent both an increase in tolerance as well as prevent a gradual loss of the analgetic effect in their patients. I personally experienced this when I stopped taking morphine after years of use and started taking Methadone instead. In the first two days I didn't notice anything besides having no withdrawals, but from the third day onward I started to feel a strong sense of euphoria and generally the whole spectrum of positive effects associated with opioids. I felt like I was back in my opioid naive days. This lasted two weeks after which I switched back to morphine and had the same effect. Rinse repeat. I have no idea why this works but here is my theory: could it be that opioid agonists' cross tolerance directly correlates with their structural similarity? What I mean by that is this: imagine you rotate between morphine and oxycodone every three days. Your tolerance still increases because they are both part of the same "family" so to speak, that is they are both 4,5-epoxymorphinans and therefore structurally too similar in order to not be cross tolerant. Now compare this with Methadone. Methadone as a 3,3-diphenylpropylamine is structurally completely different to morphine. In fact it is so different that just by looking at the structure one could assume that those are two completely different substances with completely different effects. So I'm thinking maybe the body interprets it that way when it gets this totally different molecule that works like an opioid but has a very different structure and hence the lack of cross-tolerance.
I also noticed this with Levorphanol that I am taking since a year. Whether I was previously on methadone or morphine, I feel good effects when I switch to an opioid from a different class.

Or is the cause somewhere else entirely? Do you guys have similar experiences? Is there maybe some list with opioids that share little to no cross-tolerance to each other? Studies are welcome.

 

[SpeedballSteve]

I was reading about this recently, a post by Duchess Von Dilaudid AKA Oxycosmopolitan. Incomplete Cross Tolerance is what it's called.

Unrelated but I was just reading a diff thread by you; are you familiar with isomethadone? She ranks it as one of the most euphoric opioids shes tried,.

 

[4DQSAR]

Isomethadone? That's a side-product of the original synthesis of methadone and isn't considered a potent analgesic. Maybe it has some other effect(s), but as an opioid, I don't understand that.

There is a stack of research by Jannsen and others and so isomethadone was tested quite a lot - but I guess indiosyncratic responses are a thing. It held a [P] licence for decades as an antitussive.

 

[someguyontheinternet]

tolerance to opioids is caused by cyclic amp basically. activation of the mu opioid gpcr causes blockade of adenylate cyclase leading to reduction in cAMP. the cell responds by increasing transcription of adenylate cyclase to get cAMP levels back to normal range

so that means you've got excess adenylate cyclase making a ton extra cAMP when the opioid is removed. any mu opioid agonist will have this same action regardless of beta arrestin selectivity afaik

sorry this is mostly off memory so some small details might be wrong

 

[chippermonk]

This article is interesting on this topic, it's worth reading in detail for more than just the headline. The study says that combining kratom and morphine can reduce the development of tolerance because kratom works by a somewhat different pathway, not increasing cAMP. ( I'm a simple layman, of course)

https://www.mdpi.com/1420-3049/18/1/666

Personally, I'm not comfortable combining regular opioids and kratom, though. Kratom has many alkaloids working in many ways. Some safety questions for me, and, also, different batches of kratom are going to vary in terms of the ratios of particular alkaloids, so you can't get the consistency that you do with a pharmaceutical. ( but the study does attempt to look for damage to liver and kidney function, and does conclude that it is safe, at least a certain dosage level. Dunno...)
One question I have about this: on the one hand, the study concludes that you can avoid tolerance by combining the two ( at least, for the limited time frame of this study, 9 days I think it was?). On the other hand, here on BL I have read people complaining that kratom does increase tolerance, plus also that it ruins the high for regular opioids. This latter observation makes me wonder if people are judging it by the perception of euphoric effects, rather than by simple analgesia effectiveness... I mean, these researchers are testing animals for pain sensitivity, but not asking them whether they get a buzz off of it

 

[Conky]

There was a poster here that talked about using memantine as he came off a 600mg morphine daily regime. Can't remember exactly what he said but it involved the symptoms of morphine WD being significantly easier. But he kept using the memantine daily and developed a fairly high tolerance.

Unfortunately his account is gone now so can't @ him.

 

[chippermonk]

I don't know, I'm trying to make sense of that study I posted regarding using kraton together with morphine to keep morphine tolerance low. It's all too complicated for me to reach a good opinion. I don't understand all the interactions of different CYPs and such. Kratom has a lot of interactions with CYPs, for example, inhibiting CYP2D6, which is involved in metabolizing codeine, tramadol, oxycodone, and hydrocodone, but not morphine or fentanyl. So maybe the interaction is different for different opioids. And besides, preventing tolerance buildup is not the same as rolling back tolerance, or circumventing tolerance.

 

[DeathIndustrial88]

Every opioid is unique & they attach to & agonize/antagonize so many different receptors.

I've noticed for example that I can switch from heroin to bupe & even though the heroin is obviously the one to get a good buzz from, I still sort of feel a distinct "buzz" or effect that only comes from bupe, while also feeling the withdrawal from heroin.

Tramadol for example affects way more than opioid receptors, creating a unique effect or "buzz".

There are 3 main opioid receptors (and more, but they are outdated & not technically considered opioid receptors anymore).
These receptors are MU, DELTA & KAPPA.
And an opiate or opioid can attach to these 3 receptors in various ways. One might agonize mu (which is where most of the effects come from), while only agonizing delta & not kappa. Some may be partial agonists at mu, but an antagonist at delta & kappa. Some might agonize all 3 but might it might agonize Kappa or Delta much more than mu.

And not only are these 3 receptors responsible for everything, but these receptors also have "sub-receptors", like mu1, mu2, mu3, etc... It gets very complex.
Most of the "euphoric" opioids will attach to mu2 (or mu3, depending on your sources). And some attach to all 3.

An opioid can be a strong mu agonist, but not affect mu2, meaning less euphoria, less pain relief, etc... Buprenorphine for example is an incredibly potent partial mu agonist that binds stronger than most opioids, but since it does not affect the sub-receptors in the same way heroin or other opioids would, it doesn't cause as much "euphoria" or various other effects.

Some sub receptors are just responsible for side effects, like sedation, constipation, miosis, etc..
I've noticed whenever I use hydrocodone, I barely get any miosis, possibly because it's not affecting the receptor responsible for miosis as much as another opioid would. Buprenorphine again for example pins the hell out of my pupils to the point where they're almost gone completely from my eyes, but I can feel totally sober at the same time.

So while this doesn't exactly have to do with tolerance, it does show you how complex every individual opioid can be & their effects. So switching opioids when one stops working can be really useful because another opioid might bring pain relief back by agonizing receptors in a different way than the previous opioid can. And depending on people's genetics & biology, they may find themselves feeling okay again, at least temporarily.

I also think this is why some opioids don't share total cross-tolerance, because every opioid is going to agonize your receptors in unique ways. You may have been on an opioid that was only agonizing a receptor so much, which helped at first, but another opioid might do a better job. And you can also drop some tolerance to the other opioid, depending on all kinds of various factors, such as potency & receptor profile.

For example you could be taking morphine, it stops working, you switch to tramadol & it's TAAR1 (serotonin release properties) and it's full agonist metabolite might suddenly make you feel great again. And since tramadol is a bit less potent than morphine, it's possible that when you go back to morphine, you may feel it again.

There's so many complex possibilities I think.

Honestly, I wish they'd offer people on maintenance opioids the ability to rotate too. I mean the maintenance opioids are meant to help with cravings, but they're not gonna help if they're not doing anything. lol

 

[4DQSAR]

I believe that the 'receptor formally known as ORL1' is now termed the Nociceptin receptor, often shortened to NOP. Unlike the others it doesn't appear to have been assigned a Greek character but is certainly involved in the action of classic opioids. There are some selective NOP ligands but as far as I can tell, while NOP provides a lot of analgesia in animal models, in humans it appears MOR (mu opioid receptor) activity is still important in producing analgesia.

 

[DeathIndustrial88]

I believe that the 'receptor formally known as ORL1' is now termed the Nociceptin receptor, often shortened to NOP. Unlike the others it doesn't appear to have been assigned a Greek character but is certainly involved in the action of classic opioids. There are some selective NOP ligands but as far as I can tell, while NOP provides a lot of analgesia in animal models, in humans it appears MOR (mu opioid receptor) activity is still important in producing analgesia.

Yes, I totally forgot about NOP, but this is a good point too.

I think the Sigma receptors were once considered opioid receptors too, but they're not anymore.
I do find DXM & methamphetamine to be slightly analgesic, as those are the only 2 "Sigma" drugs I've ever tried. But the analgesia could just be from dopamine release too.

Some opioids affect the Toll-like receptor, which is starting to get out of my area of knowledge, but I believe those receptors deal with inflammation & the immune system & probably aren't necessarily playing a role in making opioids more pain relieving or not, I would suppose anyway.

I think opioids/opiates are just complex. They're all so individual & unique & its more complex than just "well I have a tolerance to this opioid, so I won't be able to feel anything from X, Y, Z opioid"... Which is just too simple of a way of thinking.

I know you (4DQSAR) are probably well aware of all of this, so I'm mostly just writing this reply out so that anyone cruising the internet or looking for info, or just simply trying to educate themselves can see it.

 

[4DQSAR]

It's still open to debate if each of the classes of receptor have their own subtypes or if it's an artifact of genetics. I find it interesting that when yet another type was discovered, it was assigned the Greek letter Zeta (ζ) since it's activity is SO different.

But yeah, Paul Ehrlich's vision of medicines being the 'magic bullet' is, as we now realize, impossible for many reasons. So there are almost certainly going to be other receptors such medicines also bind to.

That's why I will NEVER tell someone that a drug is safe. I may suggest some drugs are more toxic than others, but dosis sola facit venenum.

 

[DeathIndustrial88]

It's still open to debate if each of the classes of receptor have their own subtypes or if it's an artifact of genetics. I find it interesting that when yet another type was discovered, it was assigned the Greek letter Zeta (ζ) since it's activity is SO different.

But yeah, Paul Ehrlich's vision of medicines being the 'magic bullet' is, as we now realize, impossible for many reasons. So there are almost certainly going to be other receptors such medicines also bind to.

That's why I will NEVER tell someone that a drug is safe. I may suggest some drugs are more toxic than others, but dosis sola facit venenum.

Yeah I've seen some sites that say mu2 is responsible for the best euphoria & "high", while another site says it's "mu3" that's responsible for it.
Information about sub-receptors seem scarce & choppy.

Hell I found a government pdf the other day that's still up & it has so much outdated information about buprenorphine. lol Saying Suboxone causes withdrawals because of naloxone & all that. Except everyone knows buprenorphine itself causes precipitated withdrawal. I couldn't believe they still had such outdated misinformation up.

I think the sub-receptor thing might make some sense though. I thought heroin was a great opioid, but when I first tried fentanyl, I thought it sucked. And it completely lacked the euphoria of heroin or anything. And I thought "Why? Fentanyl is more potent, so shouldn't it be more euphoric?"... And that's when I learned about sub receptors. And although I can't find any particular information about it, I have a feeling that heroin probably affects mu2 (or mu3, whichever one it is lol) more so than fentanyl. And that's why even though fentanyl is stronger, it doesn't give the same euphoria.

So this made me question things & I realized that mu agonism can't be the sole thing that makes an opioid feel good. Cause all opioids are typically mu agonists, but they all vary in degrees of euphoria, pleasure, side effects, etc...

So that's when I discovered the sub-receptor thing & it seems to make some sense to me, but finding information about it actually not that easy. And as you pointed out, genetics might have something to do with it. Cause I'm sure for every person like me who thinks diacetylmorphine is more euphoric, there are 50 others who are going to say fentanyl is more euphoric for them. lol So who knows.

 

[Opiophiliclab]

Every opioid is unique & they attach to & agonize/antagonize so many different receptors.

I've noticed for example that I can switch from heroin to bupe & even though the heroin is obviously the one to get a good buzz from, I still sort of feel a distinct "buzz" or effect that only comes from bupe, while also feeling the withdrawal from heroin.

Tramadol for example affects way more than opioid receptors, creating a unique effect or "buzz".

There are 3 main opioid receptors (and more, but they are outdated & not technically considered opioid receptors anymore).
These receptors are MU, DELTA & KAPPA.
And an opiate or opioid can attach to these 3 receptors in various ways. One might agonize mu (which is where most of the effects come from), while only agonizing delta & not kappa. Some may be partial agonists at mu, but an antagonist at delta & kappa. Some might agonize all 3 but might it might agonize Kappa or Delta much more than mu.

And not only are these 3 receptors responsible for everything, but these receptors also have "sub-receptors", like mu1, mu2, mu3, etc... It gets very complex.
Most of the "euphoric" opioids will attach to mu2 (or mu3, depending on your sources). And some attach to all 3.

An opioid can be a strong mu agonist, but not affect mu2, meaning less euphoria, less pain relief, etc... Buprenorphine for example is an incredibly potent partial mu agonist that binds stronger than most opioids, but since it does not affect the sub-receptors in the same way heroin or other opioids would, it doesn't cause as much "euphoria" or various other effects.

Some sub receptors are just responsible for side effects, like sedation, constipation, miosis, etc..
I've noticed whenever I use hydrocodone, I barely get any miosis, possibly because it's not affecting the receptor responsible for miosis as much as another opioid would. Buprenorphine again for example pins the hell out of my pupils to the point where they're almost gone completely from my eyes, but I can feel totally sober at the same time.

So while this doesn't exactly have to do with tolerance, it does show you how complex every individual opioid can be & their effects. So switching opioids when one stops working can be really useful because another opioid might bring pain relief back by agonizing receptors in a different way than the previous opioid can. And depending on people's genetics & biology, they may find themselves feeling okay again, at least temporarily.

I also think this is why some opioids don't share total cross-tolerance, because every opioid is going to agonize your receptors in unique ways. You may have been on an opioid that was only agonizing a receptor so much, which helped at first, but another opioid might do a better job. And you can also drop some tolerance to the other opioid, depending on all kinds of various factors, such as potency & receptor profile.

For example you could be taking morphine, it stops working, you switch to tramadol & it's TAAR1 (serotonin release properties) and it's full agonist metabolite might suddenly make you feel great again. And since tramadol is a bit less potent than morphine, it's possible that when you go back to morphine, you may feel it again.

There's so many complex possibilities I think.

This makes an awful lot of sense. So it has a lot to do with the agonization of sub-receptors it seems. Or so it is postulated. Thanks for all of that valuable information. Lots to reflect on for me.

Honestly, I wish they'd offer people on maintenance opioids the ability to rotate too. I mean the maintenance opioids are meant to help with cravings, but they're not gonna help if they're not doing anything. lol

That's why MT as it exists today is totally pointless except for preventing people from financially wrecking themselves. The problem is that those oh so "educated" and "intelligent" doctors don't seem to intellectually grasp that the maintenance patient has become addicted for entirely different reasons than the pain patient, but they all treat them like pain patients. Well, if I give this junkie a daily dose of XYZ to keep his wds away, why is he still complaining? Why is he still doing other drugs?
Yeah well guess what, the maintenance patient takes opioids because the so called "side-effect" known as euphoria is not a side-effect at all. It IS the medicinal effect! Taking that away from him will ofc completely defeat the purpose of doing opioids. He won't be happy and content just because he isn't dope sick. The non-pain opioid addict is a depressive individual and uses the opioid to self-medicate his melancholia away. Actually, in some ways it could be said that all opioid addicts are pain patients, just that some suffer not from physical pain but rather psycho-emotional pain. Doctors and non-doctors alike don't understand that opioids truly are pain KILLERS in every sense of the word. As soon as society understands this, we will have liberal opioid policies. But alas, that will not happen in my lifetime I suppose. There seems to be not just ignorance at play here, but power politics too...

 

[DeathIndustrial88]

That's why MT as it exists today is totally pointless except for preventing people from financially wrecking themselves. The problem is that those oh so "educated" and "intelligent" doctors don't seem to intellectually grasp that the maintenance patient has become addicted for entirely different reasons than the pain patient, but they all treat them like pain patients. Well, if I give this junkie a daily dose of XYZ to keep his wds away, why is he still complaining? Why is he still doing other drugs?
Yeah well guess what, the maintenance patient takes opioids because the so called "side-effect" known as euphoria is not a side-effect at all. It IS the medicinal effect! Taking that away from him will ofc completely defeat the purpose of doing opioids. He won't be happy and content just because he isn't dope sick. The non-pain opioid addict is a depressive individual and uses the opioid to self-medicate his melancholia away. Actually, in some ways it could be said that all opioid addicts are pain patients, just that some suffer not from physical pain but rather psycho-emotional pain. Doctors and non-doctors alike don't understand that opioids truly are pain KILLERS in every sense of the word. As soon as society understands this, we will have liberal opioid policies. But alas, that will not happen in my lifetime I suppose. There seems to be not just ignorance at play here, but power politics too...

I completely agree here.

As much as I hate to admit, a big chunk of why I ended up dependent on opioids was due to psychic/emotional pain. Which often manifests through physical pain as well. They say depression can affect some of the same parts of the brain as physical pain.

I think some docs might understand this but then this is why they push so heavily for "therapy" and having a psychiatrist & all that jazz. Which can be helpful for maybe some mild cases but for me, I've been at it for numerous years. The person craving opioids every day is not a happy person & I don't think they ever will be. I've gone through all my "traumas" 5000 times with 20 different therapists, doctors, blah blah. Nobody even knows what to do with me. lol I don't even consciously care about everything I've gone through in the past or whatever they might believe causes my "addiction". It's just a part of who I am now, we all have crutches we rely on to get us through our existence here on Earth. If anything, it's just reaffirmed my belief that people deserve more autonomy over the bodies & well-being. We're cool with feeding people SSRIs for depression, but the idea of some one using opioids for it is just some how "too taboo" for people still.

I've been on bupe for almost 10 years now. It's been a little helpful. It does keep me from binge drinking alcohol, which I was finally able to quit as well by having some kind of opioid I could take every day, instead of bouncing back n forth from having a few weeks of opioids/heroin & then back into withdrawals until the next time came around. But bupe has so many downfalls. I'm WAY more tired & sedated on bupe than I ever was on heroin or tramadol. I mean, I got tired & sedated on heroin/trams as well, but it was a "comfortable" tired/sedated that I could pull myself out of. Most of the time I felt too good to sit around being sedated, so I'd get up & do things & engage with life. But on bupe, I'm just so fuckin' tired, in an uncomfortable way, that I have to nap & sleep all the damn time. There's no "push" or desire to do anything on bupe (there is some times, it's random & rarely happens after all these years, but I do have days where bupe will make me wanna get up & do shit & I'll feel alright, but it's never as good as other opioids), but it was the opposite on full agonists. So it's just hilarious to me that society IS okay with me being heavily dependent on a partial agonist that's 50x more potent than morphine, as long as it doesn't make me feel good & basically flattens my entire mood/thoughts for the whole day & makes me so tired that I have to nap every few hours or my body starts fighting with itself.

And yeah, no problem about the sub-receptor thing
As the guy after that pointed out, some of the studies on it are a bit shifty. I've read some that say mu2 is responsible for heroin's euphoria, while another site says it's actually mu3. So I suppose we can't say the sub-receptor thing is concrete science yet. But I was once curious why some opioids had better euphoria than others. Because if it was only just the mu-receptors in general that caused euphoria, then most opioids would just feel almost identical, except we all know they don't. Some opioids stimulate me, some sedate me, some both stimulate & sedate me. Some have euphoria,. some have a little, some have no real euphoria at all. Some cause histamine release, some don't & on & on. And the sub-receptor theory is the best thing I could find that would explain why this is. It sounds plausible to me. And because of this, I think it would also play into cross-tolerance & why opioid rotation can be a great thing!

 

[Tetrapharmakos]

I think the issue with something like you mention is that, even if you can find this kind of effect of experiencing uncharacteristically low tolerance due to opioid change or some combination of drugs,

In my opinion, (for what it's worth, lol. To be clear, I'm not claiming to know what I am talking about.)

I just don't believe it would be something you can continue consistently and continue to get the same low-tolerance kind of beneficial effects over the long term.

Our brains seem to love being in homeostasis, and in my experience and from what I've read on the experiences of others, it seems even when trying different types of work around to trick your way out of tolerance by changing opiates, the brain will eventually catch on to the cycles happening over time and the effect will lose its magic.

Even SR-17018 which I can personally say is mind blowing for its ability to detox from opiates without having to experience any acute withdrawal symptoms at all except maybe a bit of fatigue-

SR-17018 does also lower tolerance much, much faster than your tolerance would lower naturally from staying abstinent of using opiates, but despite this substance being a legit "too good to be true" but somehow actually real cheat code for avoiding withdrawals, the effects on a lowered tolerance are not something you can truly benefit from.

Despite relatively rapid reduction in tolerance to opiates with SR-17018, your tolerance will again rise to its previous levels even more rapidly if you continue to use opiates again. Our brains seem to remember, and once it recognizes consistent opiate use again, quickly rewinds tolerance back to the high levels it was prior to using SR-17018 for detox and tolerance reduction.

 

[Skorpio]

I think the Sigma receptors were once considered opioid receptors too, but they're not anymore.
I do find DXM & methamphetamine to be slightly analgesic, as those are the only 2 "Sigma" drugs I've ever tried. But the analgesia could just be from dopamine release too.

The sigma receptors (especially sigma 1) are so fucking weird. They sit on the endoplasmic reticulum and cell surface and increase calcium release from other pathways. Completely unique structure too, no resemblance to GPCRs or ion channels.

I’ve always been interested in them because it seems that they have a super broad range of agonists, and that the agonists tend to be pretty well liked drugs. I’m just gonna copy an abbreviated list from Wikipedia focusing on the bangers: ketamine, pcp, 3-meo PCP, DXM, methylphenidate, methamphetamine, cocaine, DMT, and pentazocine. I left out tool ligands and various antidepressants which are agonists as well. This cluster of compounds seems to have very little in common other than all being drugs of abuse (to varying degrees).

I find that it is a very understudied modulator of signaling.

 

[4DQSAR]

Ah, I did not know cocaine was a sigma agonist.

I will do some reading...

 

[DeathIndustrial88]

The sigma receptors (especially sigma 1) are so fucking weird. They sit on the endoplasmic reticulum and cell surface and increase calcium release from other pathways. Completely unique structure too, no resemblance to GPCRs or ion channels.

I’ve always been interested in them because it seems that they have a super broad range of agonists, and that the agonists tend to be pretty well liked drugs. I’m just gonna copy an abbreviated list from Wikipedia focusing on the bangers: ketamine, pcp, 3-meo PCP, DXM, methylphenidate, methamphetamine, cocaine, DMT, and pentazocine. I left out tool ligands and various antidepressants which are agonists as well. This cluster of compounds seems to have very little in common other than all being drugs of abuse (to varying degrees).

I find that it is a very understudied modulator of signaling.

That is pretty weird! So they're just inside the little pathways of a cell that carry things around? That seems like such a microscopic level that my drug addled brain can't even comprehend it right now. lol

We clearly must have them for one reason or another.
It's hard to explain but I feel like out of all of those drugs that I've tried (dxm, methylphenidate, cocaine, meth, etc..) there is some kind of abstract "feeling" on every one of those drug which I can say makes them feel like one another, but in a really weird roundabout way. It's just some way that they change my psyche & make the world seem more saturated in color & gives me this "burnt out" mental state, but not necessarily in a bad way, just in a totally don't give a shit about anything right now type of feeling. Lol Wish I had a better way to explain this! lol I've always wondered if the "sigma" aspect of these drugs played any role in that unique feeling, even if I feel it for a fleeting few moments on one drug & not so much on another, it's still a type of "state" that I can't grasp or put into words.

 

[4DQSAR]

Yeah, Skorpio is someone who REALLY knows their stuff and it just shows when they can just drop in a little comment to get us all thinking.

Didn't Confuscius say something along the lines of 'a teacher for a day is a parent for life'?

I guess we all have Skorpio. A really decent person.

 

[Skorpio]

That is pretty weird! So they're just inside the little pathways of a cell that carry things around? That seems like such a microscopic level that my drug addled brain can't even comprehend it right now. lol

We clearly must have them for one reason or another.
It's hard to explain but I feel like out of all of those drugs that I've tried (dxm, methylphenidate, cocaine, meth, etc..) there is some kind of abstract "feeling" on every one of those drug which I can say makes them feel like one another, but in a really weird roundabout way. It's just some way that they change my psyche & make the world seem more saturated in color & gives me this "burnt out" mental state, but not necessarily in a bad way, just in a totally don't give a shit about anything right now type of feeling. Lol Wish I had a better way to explain this! lol I've always wondered if the "sigma" aspect of these drugs played any role in that unique feeling, even if I feel it for a fleeting few moments on one drug & not so much on another, it's still a type of "state" that I can't grasp or put into words.

A lot of antidepressants hit sigma receptors too. I will give one caveat, that my bias is very much toward intracellular signaling, and I probably miss a lot of nuance when it comes to circuit level effects (like different gaba A receptor compositions, where their main difference in activity is where they are located).

If I ever researched drugs and their effects directly, I would love to probe this pathway (ie see how sigma receptor knockouts affect mouse drug preferences), but at this point it doesn’t look like I am on that path (though things are currently very up in the air).

Yeah, Skorpio is someone who REALLY knows their stuff and it just shows when they can just drop in a little comment to get us all thinking.

Didn't Confuscius say something along the lines of 'a teacher for a day is a parent for life'?

I guess we all have Skorpio. A really decent person.

Aww thanks!