THC is a Allosteric Modulator of Opioid Mu and Delta

[airsh0w]

This is news to me. I'm guessing its a positive allosteric modulator. What are the implications if this is true?


REF:

http://www.ncbi.nlm.nih.gov/pubmed/16489449

This is what is going on. Cannabidiol and THC (factor of 12 and 2 respectively)[so 6 times more so cannabidiol] are lowering the affinity of opioids (at least the agonist they used) to the Mu and delta sites by allosterically altering the conformation of the sites but this doesn't mean efficacy is being effected but it could. It could increase it or decrease it. Just because the opioid didn't fit as tight doesn't mean its not activating the g-proteins "worse" or "better".

 

[Amu]

Assuming it is positive, it would enhance THC and CBD's pain relieving and perhaps anti-depressant properties indirectly by allowing endorphins and exogenous opiates to bind to the receptors more strongly.

 

[SNR]

Interesting. This could account for cannabis really (I mean REALLY) boosting the effects of opiates for me.

 

[airsh0w]

Interesting. This could account for cannabis really (I mean REALLY) boosting the effects of opiates for me.

Nice and with enough oxytocin, an NMDA antagonist, and or a CCKB inhibitor you will not gain opioid tolerance.

 

[Bucklecroft Rudy]

Nice and with enough oxytocin, an NMDA antagonist, and or a CCKB inhibitor you will not gain opioid tolerance.

False hope my man - but you'll find that out soon enough. Tolerance is the hydra of opiates. Youll need to control your cck,nmda,g protein,peroxynitrite and the list goes on I use ULD naltrexone with proglumide and Magnesium+zinc taking care of it all except peroxy. We still dont have a clue how to completely stop toleance however.

 

[airsh0w]

False hope my man - but you'll find that out soon enough. Tolerance is the hydra of opiates. Youll need to control your cck,nmda,g protein,peroxynitrite and the list goes on I use ULD naltrexone with proglumide and Magnesium+zinc taking care of it all except peroxy. We still dont have a clue how to completely stop toleance however.
+

Yeah probably was. Tolerance is the hydra all of drugs through direct or indirect means.

 

[Bucklecroft Rudy]

Yeah probably was. Tolerance is the hydra all of drugs through direct or indirect means.

Dont want to derail the thread but tolerance is literally just the brains way of achieving balance.Opiates disrupt the endorphin system - imbalance - so the brain starts to set processes in motion leading to tolerance. Im using poppy pods at the moment and for the past 2 maybe 3 months my tolerance is stable which for a pod habit is very unusual. I know that it will eventually climb up however the rate will be almost neglibly slow. You have to remember that ive been an addict for 5 years too so my tolerance should be huge. I havent taken a break of longer than 2 weeks in all that time either so I must be doing something right.

 

[PsychedelicPeptide]

The dissociation of 3H-DAMGO induced by naloxone 10 microM (half life time of 7+/-1 min) was accelerated by cannabidiol and THC (at 100 microM, each) by a factor of 12 and 2, respectively.

The quoted line says the dissociation of an agonist (DAMGO) induced by an antagonist (naloxone) is sped up by THC. I'm not sure you can call this allosteric modulation because the action of THC is tertiary to the (secondary) action of the antagonist to forcibly remove the (primary) agonist from the binding site. If it were simply THC modulating the action of DAMGO, then it is allostery, but I have never seen a result like this. They call THC allosteric but I'm not sure that is right because it influences how an antagonist behaves, and antagonism is not what the native ligands for the opioid receptor do. That is, THC does not modulate the normal biological behavior of the opioid receptor. I could be wrong though...

anyways I'm not really sure if it means anything important unless you are using opioid antagonists.

 

[crOOk]

Are there any impressive clinical studies linking pot to lower needed morphine doses for an equally efficient pain management? On it's own pot seems to do the opposite for my (usually entirely bearable) joint pain to be honest. To me pot makes it easier to cope with pain though, an effect I can only assume to be much more important with more intense chronic pain and more pronounced decreases in quality of life.

 

[crOOk]

The quoted line says the dissociation of an agonist (DAMGO) induced by an antagonist (naloxone) is sped up by THC. I'm not sure you can call this allosteric modulation because the action of THC is tertiary to the (secondary) action of the antagonist to forcibly remove the (primary) agonist from the binding site. If it were simply THC modulating the action of DAMGO, then it is allostery, but I have never seen a result like this. They call THC allosteric but I'm not sure that is right because it influences how an antagonist behaves, and antagonism is not what the native ligands for the opioid receptor do. That is, THC does not modulate the normal biological behavior of the opioid receptor. I could be wrong though...

anyways I'm not really sure if it means anything important unless you are using opioid antagonists.

Doesn't allosteric in it's broadest translation just mean having a different binding site?

edit: wiki agrees: "In biochemistry, allosteric regulation is the regulation of an enzyme or other protein by binding an effector molecule at the protein's allosteric site (that is, a site other than the protein's active site)."
it basically just means that pot wont bind to the same site as morphine if i am not mistaken, i cant say i know much about opiate receptors.
please dont take this as an offense or anything, but i sometimes wonder why people do not use more wikipedia. it has gained such a bad reputation, but when it comes to biochemistry and physiology, it can be an incredibly rich and surprisingly accurate pool of quickly and freely accessible, very well-structured information. im not advertising for wikipedia, i just think its among the greatest things humanity has ever created in a common effort.

 

[airsh0w]

Doesn't allosteric in it's broadest translation just mean having a different binding site?

edit: wiki agrees: "In biochemistry, allosteric regulation is the regulation of an enzyme or other protein by binding an effector molecule at the protein's allosteric site (that is, a site other than the protein's active site)."
it basically just means that pot wont bind to the same site as morphine if i am not mistaken, i cant say i know much about opiate receptors.
please dont take this as an offense or anything, but i sometimes wonder why people do not use more wikipedia. it has gained such a bad reputation, but when it comes to biochemistry and physiology, it can be an incredibly rich and surprisingly accurate pool of quickly and freely accessible, very well-structured information. im not advertising for wikipedia, i just think its among the greatest things humanity has ever created in a common effort.

You are right about all that. This is what is going on. Cannabidiol and THC (factor of 12 and 2 respectively)[so 6 times more so cannabidiol] are lowering the affinity of opioids to the Mu and delta sites by allosterically altering the conformation of the sites but this doesn't mean efficacy is being effected but it could. It could increase it or decrease it. Just because the opioid didn't fit as tight doesn't mean its not activating the g-proteins "worse" or "better".

 

[crOOk]

You are right about all that. This is what is going on. Cannabidiol and THC (factor of 12 and 2 respectively)[so 6 times more so cannabidiol] are lowering the affinity of opioids to the Mu and delta sites by allosterically altering the conformation of the sites but this doesn't mean efficacy is being effected but it could. It could increase it or decrease it. Just because the opioid didn't fit as tight doesn't mean its not activating the g-proteins "worse" or "better".

Thanks a lot for your reply!

But wait the affinities are lowered? How exactly? can you tell me which equilibrium constants (dissociation/affinity K) changes in what way? From my knowledge opioids pain dulling effects are mainly caused by opioids being direct agonists for the receptors you mentioned with euphoria being to some large degree attributed to the mu-or if I'm not mistaken. If the dissociation constants for important exogenous opioids at their common site rises (which is my understanding of affinity), I would expect a weaker response to the same opioid dosage. I assumed:
Higher dissociation constant = lower affinity -> cellular responses to a given ligand activity are lowered -> less pain dulling

While I can't say it's an amazing combination like many do, I'd say from personal experience that opiate effects are definitely increased by a whole lot when combined with pot btw, I have an idea of a few mechanisms through which the response to the same ligand at the same local activity can be (allosterically) modified. Not that it would matter here, but sometimes it's of help to understand where someone else stands. The whole biochemistry and physiology thing is very very new to me and while I'd say there's a good basic understanding of possible mechanics, I am pretty much a total noob on cb receptors and opioid receptors. when i seem a little arrogant or sceptic its not because i am actually doubting your words, just questioning and reassuring myself to understand the basics better. if something seems really fishy, id surely look it up thoroughly first. right now im just not sure if i didnt understand you properly (therefore the lengthy explanation) or if you have a typo in there.


Edit: Ooooh you were probably talking about the "efficacy" when the same relative amount of receptors has a ligand bound to them at a given time vs. me understanding "efficacy" as efficacy of the same given opioid dosage. :D Is my use of the word actually misleading and is there a better phrasing or was this just a hardly avoidable misunderstanding?
ive recently noticed that some articles refer to both antagonists and agonists as "ligands" even if their properties have thoroughly been studied and they only have some cryptic research name. this becomes extremely confusing in an extensive sigma receptor review i recently read, must have over 20 pages without any graphics... :D its imho based on an awful type of ignorance that either assumes all readers are as deep into the subject as researchers or simply value their narcisstic ego and ease in writing over reader friendliness. maybe i just dont understand the code behind the research names or id be remembering them better. i personally cant see a reason to refer to an outside of research labs unknown substance with the word "ligand" instead of agonist or antagonist if they are at another place descrbibed as such in the same article... sigh. aimless rant ill bring it to a stop!


edit2: still the question remains, if pot is known as a kickass opioid booster in the scene and it lowers mu and delta opioid receptors affinty to important agonists (and most likely some antagonists as well), shouldn't the efficacy most definity be increased with both understandings of the word? id naively expect the lower affinity itself to decrease overall effects at a given dosage, which (i think) could only be compensated if the binding leads to a stronger response somehow which would again mean higher efficacy after your definition. im just basing these assumptions on what people have been saying about combining pot with opioids of course, we might see a surprise and it does the opposite for pain in randoimized double blind placebo controlled trials. ill try to read the article tomorrow ;D

 

[airsh0w]

Thanks a lot for your reply!

But wait the affinities are lowered? How exactly? can you tell me which equilibrium constants (dissociation/affinity K) changes in what way? From my knowledge opioids pain dulling effects are mainly caused by opioids being direct agonists for the receptors you mentioned with euphoria being to some large degree attributed to the mu-or if I'm not mistaken. If the dissociation constants for important exogenous opioids at their common site rises (which is my understanding of affinity), I would expect a weaker response to the same opioid dosage. I assumed:
Higher dissociation constant = lower affinity -> cellular responses to a given ligand activity are lowered -> less pain dulling

While I can't say it's an amazing combination like many do, I'd say from personal experience that opiate effects are definitely increased by a whole lot when combined with pot btw, I have an idea of a few mechanisms through which the response to the same ligand at the same local activity can be (allosterically) modified. Not that it would matter here, but sometimes it's of help to understand where someone else stands. The whole biochemistry and physiology thing is very very new to me and while I'd say there's a good basic understanding of possible mechanics, I am pretty much a total noob on cb receptors and opioid receptors. when i seem a little arrogant or sceptic its not because i am actually doubting your words, just questioning and reassuring myself to understand the basics better. if something seems really fishy, id surely look it up thoroughly first. right now im just not sure if i didnt understand you properly (therefore the lengthy explanation) or if you have a typo in there.


Edit: Ooooh you were probably talking about the "efficacy" when the same relative amount of receptors has a ligand bound to them at a given time vs. me understanding "efficacy" as efficacy of the same given opioid dosage. Is my use of the word actually misleading and is there a better phrasing or was this just a hardly avoidable misunderstanding?
ive recently noticed that some articles refer to both antagonists and agonists as "ligands" even if their properties have thoroughly been studied and they only have some cryptic research name. this becomes extremely confusing in an extensive sigma receptor review i recently read, must have over 20 pages without any graphics... its imho based on an awful type of ignorance that either assumes all readers are as deep into the subject as researchers or simply value their narcisstic ego and ease in writing over reader friendliness. maybe i just dont understand the code behind the research names or id be remembering them better. i personally cant see a reason to refer to an outside of research labs unknown substance with the word "ligand" instead of agonist or antagonist if they are at another place descrbibed as such in the same article... sigh. aimless rant ill bring it to a stop!

No problem. You were mixing efficacy and affinity. They are not the same but they correlate sometimes. Efficacy is subjective and relative to the effects we are looking for. Affinity is how well it fits and efficacy depends on what its activating within the cell. Without affinity it can't plug into the receptor but without any efficacy, nothing happens (antagonist). But the terms agonist and antagonist are an oversimplication considering a receptor has many ways it can be activated. (Think 5-HT2A) You don't need equilibrium constants to know that the competitive antagonist is blocking those sites quicker after THC/Cannabidiol has changed the conformation of sites. It blocks them quicker because its having an easier time when an opioid agonist doesn't fit as well. So if the agonist is slipping out of the receptors and the antagonist blocks the site then we know for a fact the conformation is different and less in favor of opioids fitting.

An antagonist doesn't have to do much but block the site so allosteric modulation is going to be seen when a more precise agonist is slipping out of the receptor more often. But you can infer possible efficacy change from allosteric modification because of how often it occurs but we can't be sure whether it is positive or negative allosteric modulation but obviously we have anecdotal evidence from several people that leads to a reasonable hypothesis that it is a positive allosteric modulation. There are already an example of function selectivity at Mu in its regulation of the stability of dendritic spines.

Scientists over-complicate everything because it builds respect. Also they say ligand normally when they aren't sure what is going on or what it is activating and not activating. I'm glad I could help you out. It's a great field of thought but don't lose sight of the big picture.



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC545084/?tool=pmcentrez (function selectivity at Mu)
http://en.wikipedia.org/wiki/Ligand_(biochemistry)#Drug_potency_and_binding_affinity
http://en.wikipedia.org/wiki/Functional_selectivity

 

[PsychedelicPeptide]

cr00k yeah that looks ok, I wasn't really sure and didn't want to further distract myself by looking up the definition as I needed to get out the door.

Their test & assay is a bit irregular and threw me off- testing a molecule for its ability to modulate the efficacy of an antagonist.

All the allosteric modulators I know of modulate the efficacy of an agonist, so I was kind of wondering if the definition even held for antagonists.

Wiki is a great resource as well. I use it a lot, just not earlier. =P

 

[airsh0w]

Thanks a lot for your reply!

edit2: still the question remains, if pot is known as a kickass opioid booster in the scene and it lowers mu and delta opioid receptors affinty to important agonists (and most likely some antagonists as well), shouldn't the efficacy most definity be increased with both understandings of the word? id naively expect the lower affinity itself to decrease overall effects at a given dosage, which (i think) could only be compensated if the binding leads to a stronger response somehow which would again mean higher efficacy after your definition. im just basing these assumptions on what people have been saying about combining pot with opioids of course, we might see a surprise and it does the opposite for pain in randoimized double blind placebo controlled trials. ill try to read the article tomorrow ;D

It doesn't necessarily lower the antagonists efficacy by its change in conformation. That's like saying its harder to put my hand over a different type of lock. Just because their is a lower affinity for the agonist doesn't mean less efficacy for the agonist. In fact the change in conformation might actually increase the efficacy of the antagonist.

cr00k yeah that looks ok, I wasn't really sure and didn't want to further distract myself by looking up the definition as I needed to get out the door.

Their test & assay is a bit irregular and threw me off- testing a molecule for its ability to modulate the efficacy of an antagonist.

All the allosteric modulators I know of modulate the efficacy of an agonist, so I was kind of wondering if the definition even held for antagonists.

Wiki is a great resource as well. I use it a lot, just not earlier. =P

Allosteric modulators that work by changing the receptors conformation effect both the antagonist and the agonist and not necessarily the same way.

 

[SNR]

Just thought of something to add to this thread. Is there any information about cannabinoids modulating Kappa Opioid Receptors?

 

[airsh0w]

Not sure but there some interactions for sure.

http://lib.bioinfo.pl/pmid:8138952

 

[crOOk]

Just thought of something to add to this thread. Is there any information about cannabinoids modulating Kappa Opioid Receptors?

I might have two studies for you, haven't gone through them and I'm not an expert on the subject myself... So not sure how much these will help you. Drop me a line if you want the whole articles as pdf...

Repeated exposure to D9-tetrahydrocannabinol alters heroin-induced locomotor sensitisation and Fos-immunoreactivity

Abstract
The present study examined the effect of chronic exposure to D9-tetrahydrocannabinol (THC) on heroin-induced locomotor sensitisation and Fos-immunoreactivity (Fos-IR). Adult male albino Wistar rats (nZ60) were injected intraperitoneally (i.p.) 21 times with vehicle, 0.05, 0.5, or 5.0 mg/kg THC (once every 48 h for 41 days). Locomotor activity was assessed for 180 min on pre-exposure days 1, 21, and 41. Following a 2-week washout period, rats were divided into five equal groups (nZ12) and injected subcutaneously (s.c.) with vehicle or heroin (0.5 mg/kg). Locomotor activity was recorded for 240 min. In drug-naı¨ve rats, heroin significantly increased locomotor activity. THC pre-exposure further increased heroin-induced locomotion. After an interval of 2 weeks, rats pre-exposed to vehicle and 5.0 mg/kg THC in the first part of the experiment were randomly assigned to one of four treatment groups (nZ6) and injected s.c. with vehicle or 0.5 mg/kg heroin and perfused 2 h later. Fos-IR was examined in several brain regions. Acute heroin increased Fos-IR in drug-naı¨ve rats in the caudate-putamen (CPu; central, medial and dorsomedial regions), nucleus accumbens (NAC; core and shell regions), bed nucleus of the stria terminalis (BNST), lateral septum, central nucleus of the amygdala (CEA), periaqueductal grey (PAG; dorsolateral, dorsomedial, and lateral), and the EdingereWestphal nucleus. Pre-exposure to THC significantly increased heroin-induced Fos-IR in the dorsomedial CPu and the NAC (core). Conversely, THC pre-exposure reduced heroin-induced Fos-IR in the BNST, CEA, and the PAG (dorsolateral and lateral). The present study demonstrates that THC pre-exposure increases the locomotor stimulating effects of heroin and provides new evidence for the neural correlates that may underlie cannabinoid and opioid cross-sensitisation.

Source: Neuropharmacology. 2005 Dec;49(8):1189-200. Epub 2005 Aug 30.

Effect of DFosB overexpression on opioid and cannabinoid receptor-mediated signaling in the nucleus accumbens

Abstract
The stable transcription factor DFosB is induced in the nucleus accumbens (NAc) by chronic exposure to several drugs of abuse, and transgenic expression of DFosB in the striatum enhances the rewarding properties of morphine and cocaine. However, the mechanistic basis for these observations is incompletely understood. We used a bitransgenic mouse model with inducible expression of DFosB in dopa- mine D1 receptor/dynorphin-containing striatal neurons to determine the effect of DFosB expression on opioid and cannabinoid receptor signaling in the NAc. Results showed that mu opioid-mediated G- protein activity and inhibition of adenylyl cyclase were enhanced in the NAc of mice that expressed DFosB. Similarly, kappa opioid inhibition of adenylyl cyclasewas enhanced in the DFosB expressing mice. In contrast, cannabinoid receptor-mediated signaling did not differ between mice overexpressing DFosB and control mice. These findings suggest that opioid and cannabinoid receptor signaling are differentially modulated by expression of DFosB, and indicate that DFosB expression might produce some of its effects via enhanced mu and kappa opioid receptor signaling in the NAc.

Source: Neuropharmacology. 2011 Dec;61(8):1470-6. Epub 2011 Sep 3.

edit: just saw airsh0w's post which probably more useful to you... also stumbled across this:
http://www.ncbi.nlm.nih.gov/pubmed/21858449

[...]the κ-opioid receptor antagonist nor-binaltorphimine, but not the δ-opioid receptor antagonist naltrindole, attenuated THC-induced cognitive deficits, suggesting an involvement of μ- and κ-opioid receptors in this behavioral response.

 

[SNR]

Perhaps the above studies might suggest a link to why cannabinoids might cause anxiety in some people (Predisposed, upregulation of kOR's in depression, anxiety disorders, etc) and not in others?

 

[airsh0w]

Perhaps the above studies might suggest a link to why cannabinoids might cause anxiety in some people (Predisposed, upregulation of kOR's in depression, anxiety disorders, etc) and not in others?

I'm glad you just said that. Good point. When your going to stimulate activity in your brain it depends on what receptors you already have up/down regulated.