Rimonabant, salvinorin A and the cannabinoid receptors

This is the place to discuss Salvia divinorum, splendins, and the other psychoactive salvias.
bombazil
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Rimonabant, salvinorin A and the cannabinoid receptors -

Post by bombazil » Tue Jun 07, 2011 7:31 am

FrenchMachine has described a synergy between salvia and synthetic cannabinoids.

I think people have tended to assume that all/most of salvia's effects come via salvinorin A's interaction with the kappa-opioid receptor. (I've certainly thought this way, but perhaps I have a greater tendency to oversimplify than other people :? )

But I just noticed that in a scientific paper (that should be called "this is your zebrafish on salvia") that all of the effects of salvinorin A were blocked by either a kappa opioid blocker or a CB1 (cannabinoid type I) receptor blocker.

WTF??? Shouldn't there be some residual effect via the remaining receptor?

Well, so what?

It turns out that the CB1 blocker (rimonabant) used in the study is commercially available. Or was - it's been withdrawn in many countries, because of links with depression and suicidal ideation. So taking rimonanbant long-term is probably a bad idea.

But for the psychonaut with an inquiring mind, curious about the role the CB1 receptor plays in generating the subjective effect of salvia, there's a way to find out: taking rimonabant with your salvia (like a zebrafish :D ).

The only obstacle to this is getting hold of the stuff, since it was taken off the market in most countries. It looks like it might be available online, but I'm not sure. I'm also not sure about the legalities of importing non-approved but non-scheduled medications in my current jurisdiction (or elsewhere). It may also be pricey (USD150 for 30x20mg capsules, though this may just have been a particularly expensive online pharmacy).

If anyone does get round to trying this, I'd certainly be interested in hearing the results (or non-results?).

Chaotechnic
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Re: Rimonabant, salvinorin A and the cannabinoid receptors -

Post by Chaotechnic » Wed Jul 06, 2011 3:51 am

WTF??? Shouldn't there be some residual effect via the remaining receptor?
Who says there wasn't? Braida et al. 2007 only indicates that behavioral effects in zebrafish (stimulant activity at low doses and depressant activity in high doses) were blocked by rimonabant. So it might well be that certain behavioral effects of salvinorin A were blocked while other aspects of its biological activity remained intact. In fact we have indications that this is in fact true: while CB1 antagonists have been shown to block certain behavioral effects in mice (as I'll discuss in a moment), it has also been shown that they fail to block the antinociception and reduced motor activity that salvinorin A evokes in mice (Walentiny et al. 2010). Braida and colleagues also note that rimonabant might be a kappa opioid antagonist; in my review of the literature to date, this possibility has still not been entirely ruled out (although Butelman et al. at least indicates that it lacks this activity in primates, as I'll also discuss in a moment).

Another important thing to keep in mind is that this explicit relation with the cannabinoid receptor system has not been observed in primates. The initial study was done using zebrafish. Subsequent studies in rats and mice showed that the reward-based effects of salvinorin A in rats (conditioned place preference or place aversion) were blocked by rimonabant (Braida et al. 2008) and the antidepressant and anxiolytic activity of salvinorin A at low doses in rats and mice were blocked by AM251, another CB1 antagonist (Braida et al. 2009).

But the behavioral effects of salvinorin A in rhesus monkeys, specifically sedation and ptosis (a fancy word for facial relaxation) were not blocked by rimonabant (Butelman et al. 2009). And after all, we cannot expect the specific interactions of different receptor systems in response to specific ligands to be identical in such diverse vertebrates as zebrafish and rhesus monkeys. And there are indications that the involvement of the CB1 receptor system in mice is sometimes conditional; rimonabant blocks salvinorin A's ability to reduce gastric motility in mice whose gastric system has been inflamed or challenged with an endotoxin (Capasso et al. 2008; Fichna et al. 2011), but does not block salvinorin A's ability to reduce gastric motility in ordinary mice whose bowels have not been artificially inflamed (Capasso et al. 2008). Another study similarly found that CB1 and CB2 antagonists inhibited the gastric effects of salvinorin A in vitro, but in vivo the effects were predominantly due to activity at the kappa opioid receptor (Fichna et al. 2009). And a final point on this tangent: mice trained to recognize the effects of THC did not treat salvinorin A as producing the same sort of effect (Walentiny et al. 2010)... something I think most of us would regard as obvious, but pharmacologists put a lot of stock in this sort of discriminative stimulus testing when considering the pharmacological basis of a drug's effects.

And another salient point: Any involvement of the cannabinoid system must necessarily be indirect. Salvinorin A has been reported to possess either no affinity (Walentiny et al. 2010) or only very weak affinity (Braida et al. 2009; Capasso et al. 2008) at the CB1 receptor. One possible explanation of the interaction between salvinorin A and the cannabinoid receptor system is suggested by its effect on the enzyme FAAH (fatty acid amide hydrolase): salvinorin A was seen to significantly inhibit FAAH in the amygdala, as a consequence of which it may increase levels of endogenous cannabinoid receptor agonists such as anandamide (Braida et al. 2009).

At any rate, I think that pretty well summarizes the state of the literature on salvinorin A with respect to the cannabinoid system. As I recall, most of the papers I've cited can be read on Daniel Siebert's Sage Wisdom website.


Sources:Braida, D., V. Limonta, S. Pegorini, A. Zani, C. Guerini-Rocco, E. Gori, and M. Sala. 2007. "Hallucinatory and rewarding effect of salvinorin A in zebrafish: κ-opioid and CB1-cannabinoid receptor involvement" Psychopharmacology 190(4): 441-448.Braida, D., V. Limonta, V. Capurro, P. Fadda, T. Rubino, P. Mascia, A. Zani, E. Gori, W. Fratta, D. Parolaro, and M. Sala. 2008. "Involvement of κ-opioid and endocannabinoid system on salvinorin A-induced reward" Biological Psychiatry 63(3): 286-292.Braida, D., V. Capurro, A. Zani1, T. Rubino, D. Viganò, D. Parolaro, and M. Sala. 2009. "Potential anxiolytic- and antidepressant-like effects of salvinorin A, the main active ingredient of Salvia divinorum, in rodents" British Journal of Pharmacology 157(5): 844-853.Butelman, E.R., T.E. Prisinzano, H. Deng, S. Rus, and M.J. Kreek. 2009. "Unconditioned behavioral effects of the powerful κ-opioid hallucinogen salvinorin A in nonhuman primates: Fast onset and entry into cerebrospinal fluid" The Journal of Pharmacology and Experimental Therapeutics 328(2): 588-597.Capasso, R., F. Borrelli, M.G. Cascio, G. Aviello, K. Huben, J.K. Zjawiony, P. Marini, B. Romano, V. Di Marzo, F. Capasso, and A.A. Izzo. 2008. "Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis-induced hypermotility: Cross-talk between κ-opioid and cannabinoid CB1 receptors" British Journal of Pharmacology 155(5): 681-689.Fichna, J., R. Schicho, C.N. Andrews, M. Bashashati, M. Klompus, D.M. Mckay, K.A. Sharkey, J.K. Zjawiony, A. Janecka, and M.A. Storr. 2009. "Salvinorin A inhibits colonic transit and neurogenic ion transport in mice by activating κ-opioid and cannabinoid receptors" Neurogastroenterology & Motility 21(12): 1326-e128.Fichna, J., M. Dicay, S.A. Hirota, D. Traboulsi, J.A. MacDonald, A. Janecka, P.L. Beck, J.K. Zjawiony, W.K. MacNaughton, and M.A. Storr. 2011. "Differential effects of salvinorin A on endotoxin-induced hypermotility and neurogenic ion transport in mouse ileum" Neurogastroenterology & Motility (Article in Press), doi:10.1111/j.1365-2982.2011.01699.x.Walentiny, D.M., R.E. Vann, J.A. Warner, L.S. King, H.H. Seltzman, H.A. Navarro, C.E. Twine Jr, B.F. Thomas, A.F. Gilliam, B.P. Gilmour, F.I. Carroll, and J.L. Wiley. 2010. "Kappa opioid mediation of cannabinoid effects of the potent hallucinogen, salvinorin A, in rodents" Psychopharmacology 210(2): 275-284.

bombazil
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Re: Rimonabant, salvinorin A and the cannabinoid receptors -

Post by bombazil » Wed Jul 06, 2011 4:46 am

Wow - a reply! And what an informed one!

I'll have to read this carefully (armchair scientist). But the first thing I wondered were:
- what were the effects that weren't blocked in mice in the subsequent Braida study?
- how relevant are observations about local effects of salvinorin A on gut inflammation to effects in the CNS?

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kedabra
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Re: Rimonabant, salvinorin A and the cannabinoid receptors -

Post by kedabra » Wed Jul 06, 2011 8:24 am

This graph well illustrates salvinorin A's specific action as a kappa agonist

Image

bombazil
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Re: Rimonabant, salvinorin A and the cannabinoid receptors -

Post by bombazil » Wed Jul 06, 2011 12:53 pm

kedabra wrote:This graph well illustrates salvinorin A's specific action as a kappa agonist
Don't most of the rest of the bars mean it's an antagonist those other receptors? (The bottom of the scale is -40%...)

Chaotechnic
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Re: Rimonabant, salvinorin A and the cannabinoid receptors -

Post by Chaotechnic » Wed Jul 06, 2011 10:44 pm

bombazil wrote:what were the effects that weren't blocked in mice in the subsequent Braida study?
Braida et al. looked only at the reward-based effects and anxiolytic/antidepressant effects, and found that these effects were blocked by CB1 antagonists (rimonabant or AM251). That team hasn't reported on any effects that were not blocked. But in Walentiny's study, salvinorin A produced antinociception (that is, it acted as a painkiller) and reduced motor activity regardless of whether the mice were treated with rimonabant.
bombazil wrote:how relevant are observations about local effects of salvinorin A on gut inflammation to effects in the CNS?
That depends on how you look at it. I included that data because it indicates that interplay between the kappa opioid system and cannabinoid system appears to be a general property of the receptor.
kedabra wrote:This graph well illustrates salvinorin A's specific action as a kappa agonist
Yes, it is quite selective. But it's important to note that the data can't be considered entirely conclusive, as it represents only one assay protocol for each receptor. It turns out that salvinorin A also has significant affinity for the D2 dopamine receptor, but this activity is not seen when a 150 mM solution of NaCl is used as a buffer when performing the assay (Seeman et al. 2009).
bombazil wrote:Don't most of the rest of the bars mean it's an antagonist those other receptors? (The bottom of the scale is -40%...)
I think the graph is a bit misleading; the bars are actually floating above the bottom of the scale... if you look closely, the bars actually intersect right around 0% if you look at the far righthand side of the graph.


Source:Seeman, P., H.C. Guan, and H. Hirbec. 2009. "Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil" Synapse 63(8): 698-704.
Last edited by Chaotechnic on Thu Jul 07, 2011 2:28 am, edited 1 time in total.

Chaotechnic
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Re: Rimonabant, salvinorin A and the cannabinoid receptors -

Post by Chaotechnic » Thu Jul 07, 2011 3:27 am

Oh, and one other minor point from the Walentiny paper that I neglected to mention: Rimonabant was found to attenuate the dose-dependent effects of U69,593 (a synthetic kappa opioid agonist unrelated to salvinorin A) on calcium ion flux. This provides a possible mechanism for the manner in which cannabinoid antagonists modulate the effects of kappa opioid agonists. Of course further studies will be required to probe this connection further. It is not clear whether rimonabant modulates calcium ion flux (either via cannabinoid receptor interactions or independent of them), or if kappa agonists modulate calcium ion flux via interaction with cannabinoid receptors.

At this point there are more questions than answers about the role of the cannabinoid system in the effects of salvinorin A. Hopefully researchers will continue to focus on resolving these questions. Personally, I'm impressed by the amount of research that has been conducted on salvinorin A and semi-synthetic analogues thereof since it was discovered to be a potent KOR agonist back in 2002.

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kedabra
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Re: Rimonabant, salvinorin A and the cannabinoid receptors -

Post by kedabra » Thu Jul 07, 2011 8:17 am

Chaotechnic, do you have a professional interest in psychopharmacology, or did you just work this out using google? You seem to know your stuff...
Personally, I'm impressed by the amount of research that has been conducted on salvinorin A and semi-synthetic analogues thereof since it was discovered to be a potent KOR agonist back in 2002.
Plenty of research going on right here...;)
Last edited by kedabra on Thu Jul 07, 2011 11:14 am, edited 1 time in total.

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Re: Rimonabant, salvinorin A and the cannabinoid receptors -

Post by catfish » Thu Jul 07, 2011 9:43 am

right on chaotechnic
way to follow up
you are truly a scholar
;)
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Chaotechnic
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Re: Rimonabant, salvinorin A and the cannabinoid receptors -

Post by Chaotechnic » Thu Jul 07, 2011 11:23 am

kedabra wrote:Chaotechnic, do you have a professional interest in psychopharmacology, or did you just work this out using google? You seem to know your stuff...
I'm hoping to eventually make a career somewhere in the field of pharmacology, but there's not many options in my area, and I probably need to go back to school at any rate. At the moment I'm just an average worker bee who likes to research psychoactive plants in his free time.

I happen to have pretty thorough notes on Salvia divinorum because I got tired of waiting for Siebert's Divine Sage to be released (I checked archive.org, and it turns out that book has been due out every year since 1998!). A lot of information can be found by google, and local libraries are usually pretty helpful about acquiring copies of scholarly journal articles (or out-of-print foreign language books, as I found when researching the pipiltzintzintli issue) if the full text can't be found online.

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