MAPS: Salvinorin A receptor found

[coin]

Dear MAPS list members,

I have been collaborating with a group of scientists doing research into the

neuropharmacology of salvinorin A. We have discovered that salvinorin A is a

potent k-opioid receptor agonist. I am very pleased to report that our

findings are now published, so I can now share this important discovery with

you all. A pre-print copy of our new paper is available on line at: http://www.pnas.org/cgi/content/abstract/18223439 The abstract is free, but

PNAS will charge you $5 to access the full text. It should appear in print

in a few weeks. Once it is in print, it will be moved to a different section

of the PNAS web site, so the above link will probably not work at that

point.

Regards,

Daniel Siebert

The Salvia divinorum Research and Information Center http://sagewisdom.org

[Darklight]

The page you requested is not found. Damn. Is it me going 404 or what? This is the second time its happened in two daze...

[RubyTuesday]

Please excuse my ignorance, but would that be relevant to Salvia Splendens as well?

I can't get to the page either.

------------------

http://www.angelfire.com/apes/liberty

[coin]

yeah the link's broken for some reason..i can't post an address..

you just need to go to the main page and search for 'salvia'..

[coin]

http://www.pnas.org/cgi/content/abstract/182234399

[theobromos]

Fuck that, it is only an abstract and I have a copy function.

******************************************

Salvinorin A: A potent naturally occurring nonnitrogenous opioid selective agonist

Bryan L. Roth *¶, Karen Baner *, Richard Westkaemper | |, Daniel Siebert **, Kenner C. Rice , SeAnna Steinberg *, Paul Ernsberger *, and Richard B. Rothman

*National Institute of Mental Health Psychoactive Drug Screening Program, and Departments of Biochemistry, Psychiatry, Neurosciences, and Pharmacology and Nutrition, Case Western Reserve University Medical School, Cleveland, OH 44106; Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224; | |Department of Medicinal Chemistry, Medical College of Virginia, Richmond, VA 23298; **The Salvia divinorum Research and Information Center, Malibu, CA 90263; and Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892

Edited by Erminio Costa, University of Illinois, Chicago, IL, and approved July 9, 2002 (received for review April 18, 2002)

Salvia divinorum, whose main active ingredient is the neoclerodane diterpene Salvinorin A, is a hallucinogenic plant in the mint family that has been used in traditional spiritual practices for its psychoactive properties by the Mazatecs of Oaxaca, Mexico. More recently, S. divinorum extracts and Salvinorin A have become more widely used in the U.S. as legal hallucinogens. We discovered that Salvinorin A potently and selectively inhibited 3H-bremazocine binding to cloned opioid receptors. Salvinorin A had no significant activity against a battery of 50 receptors, transporters, and ion channels and showed a distinctive profile compared with the prototypic hallucinogen lysergic acid diethylamide. Functional studies demonstrated that Salvinorin A is a potent opioid agonist at cloned opioid receptors expressed in human embryonic kidney-293 cells and at native opioid receptors expressed in guinea pig brain. Importantly, Salvinorin A had no actions at the 5-HT2A serotonin receptor, the principal molecular target responsible for the actions of classical hallucinogens. Salvinorin A thus represents, to our knowledge, the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A is a psychotomimetic selective for opioid receptors, opioid-selective antagonists may represent novel psychotherapeutic compounds for diseases manifested by perceptual distortions (e.g., schizophrenia, dementia, and bipolar disorders). Additionally, these results suggest that opioid receptors play a prominent role in the modulation of human perception.

********************************************

[theobromos]

Come to think of it, that explains the antidepressant effect.

Anyone want to take bets on how fast this "heroin trip plant" will hit the headlines and be delegalised everywhere?

[waterdragon]

any minute now...

[Guest Thelema]

lets just hope there's a church somewhere using it as a sacrement...

[coin]

*cough* ahem..torsten..salvia book..new findings..inspiring, isn't it?

[Guest Thelema]

RU WRITING a salvia book Torsten?

Although i (obviously) havent read the full report of battery's they subjected SalA to, I hope they remembered to include Anandamide (?-i hope i remembered the name correctly)

[Torsten]

salvia book.... hmmm, I am sure it's on my 'to do list'

I've got the full article, but haven't read it yet. Inspiring?? not particularly.

I believe anandamide was tested in the first battery years ago - but only from (a fuzzy) memory.

[coin]

ok ok, so it's not that inspiring...something has to be tho..hmmmmmmm

[Guest reville]

i wonder what woul happen if you took

a kappa (salvia)

a Mu (morphine)

and a delta (mitragyna)

agonist all at once?

purely theoretical BTW. I know very little of Opioids

[coin]

hmm sign me up

[Guest Thelema]

so whats the first step in determining the role of k-opoid in visual processing? find some sort of visual stimulus they are deferentially responsive to?

my initial intuition is that they are involved with either body orientation or roatational aspects of vision. remembeer seiberts story about his first experience with salA, how he was "projected, and had no "behind" only "front"? Ive had similar type of experiences, where the perceptual field seems to phenomenologically remove itselfg in a widening arc of body perspective.

good doctoral thesis.

[theobromos]

Spinning and spirals seem common with low doses.

[spaced]

So if you went for a jog around the block (to stimulate production of endorphins) and then lay down with a brick placed over the forehead then you may get a similar effect. Perhaps I am oversimplifying the matter. In combination with a mu and delta antagonist then maybe the kappa receptors would be selectively stimulated.

What does 3H-bremazocine do? Is it safe / legal?

[Torsten]

Originally posted by spaced:

So if you went for a jog around the block (to stimulate production of endorphins)

Produces too much adrenaline and dopamine to give a good reading. Endorphins are more associated with pain. A 100m sprint may do the trick if you push yourself as hard as you can.... although, once again too much adrenaline.

I think an S&M mistress might know how to induce endorphins

[Guest Thelema]

The owner of my gnome recently set up an apparatus room with a spiral turning counter-clockwise on one wall.

After visual adaption, ingestion of SD produced very strange effects.

Am I the only one to see some sort of "clockwiseness" to SD? - This could also take the form of leaning to the right...pay attention next time you have 'salvia-legs'

Im not talking about minor doses either, but at larger doses one is more likely not to participate properly in the proceedings.

[DreamingNagual]

OK, mY gnome has been experimenting with salvia extracts taken while under the influence of IV morphine,The results Are somewhat confusing,Without going into detail aboot the process,The "Clockwise effect"

Was more pronounced actually sending gnomes crashing to the ground from a sitting position. After many experiments over a 1.5 month period no breakthrus were had from even the stronger salvia extracts whilst Also under the influence of opiates,But the Physycal feelings are increased by at least 5 fold,The gnomes are still studying.

[spaced]

Originally posted by Torsten:

Endorphins are more associated with pain. . . . . I think an S&M mistress might know how to induce endorphins  

Perhaps introduce this as a novel treatment for heroin addiction. I've heard of accupunture working to some extent and naloxone has been shown to block the pain relieving effects of accupunture (suggesting endogenous opioid involvement).

Also yoga - focussing on tight stretches could be helpful, at least until the government wakes up and offers medicare rebates on S & M services.

[theobromos]

An interesting abstract:

Brain Res 2002 Aug 16;946(2):262-71

kappa-Opioid and NMDA glutamate receptors are differentially targeted within rat medial prefrontal cortex.

Svingos AL, Colago EE.

Department of Neurology and Neuroscience, Division of Neurobiology, Weill Medical College of Cornell University, 411 E. 69th St., 10021, New York, NY, USA

Activation of kappa-opioid receptors (KOR) in the medial prefrontal cortex (mPFC) modulates excitatory transmission, which may involve interactions with N-methyl-D-aspartate (NMDA) glutamate receptors. We investigated possible anatomical correlates of this modulation by using dual labeling electron microscopy to examine the cellular distributions of antibodies raised against KOR and the R1 subunit of the NMDA receptor (NR1). KOR immunoreactivity primarily was localized to plasma and vesicular membranes of axons and axon terminals that were morphologically heterogeneous. A small proportion of KOR immunoreactivity was associated with cytosolic compartments of dendrites and membranes of glial processes. NR1 labeling was mainly postsynaptic, associated most often with membranes of cytoplasmic organelles in cell bodies and large dendrites and plasmalemmal surfaces of distal dendrites. The remaining NR1-labeled profiles were axonal profiles and glial processes. Of all cellular associations between labeled profiles, the majority were KOR-labeled axons that contacted NR1-immunoreactive dendrites or cell bodies. Occasionally the two antigens were colocalized in axon terminals that formed either asymmetric synapses or displayed varicose morphology. KOR and NR1 also were colocalized within dendrites, and rarely were observed in the same cell bodies. Occasionally glial processes coursing adjacent to axo-spinous appositions expressed both KOR and NR1 immunoreactivity. These results indicate that ligand activation of KOR or NMDA receptors differentially modulates excitatory transmission in the mPFC through pre- and postsynaptic mechanisms, respectively. The data also suggest more minor roles for colocalized KOR and NMDA receptors in shared regulation of presynaptic transmitter release, postsynaptic responsivity, and glial function.

[Guest Thelema]

interesting research, Theo.

I just thought of a far less messy way to begin with for salvia(ie. k-opoid agonist) research, although MOJO RISIN has an interesting approach. We are now in a position to discover selective opoid-ANTagonist patterns of activation.

This simple experiment to begin with:

"Does naltrexone diminish the k response,or block mitragynine?" Very easy experiment.

Id also like to see whether MJ affects the k-opoid region. I have a suspicion that MJ contains many other diterpenoids other than THC in form...some of these i believe may trigger k-opoid responses. A good way to test this is to actually do an acetone extract of MJ at concentration. This way you raise the THC/other neo clerodane diterpenoid ratio, plus capturing any tryptamine alkaloids.

[theobromos]

In case it passed anyone by, the NMDA sytem is associated with the actions of the dissociatives - DXM, ketamine, nitrous oxide, PCP, high dose ibogaine, for example.

Seek and ye shall find. Where they write "micro" read "mu"

J Neurosci 2002 Feb 1;22(3):1146-54

Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors.

Ghozland S, Matthes HW, Simonin F, Filliol D, Kieffer BL, Maldonado R.

Laboratori de Neurofarmacologia, Facultat de Ciencies de la Salut i de la Vida, Universitat Pompeu Fabra, 08003 Barcelona, Spain.

Repeated THC administration produces motivational and somatic adaptive changes leading to dependence in rodents. To investigate the molecular basis for cannabinoid dependence and its possible relationship with the endogenous opioid system, we explored delta9-tetrahydrocannabinol (THC) activity in mice lacking mu-, sigma- or kappa-opioid receptor genes. Acute THC-induced hypothermia, antinociception, and hypolocomotion remained unaffected in these mice, whereas THC tolerance and withdrawal were minimally modified in mutant animals. In contrast, profound phenotypic changes are observed in several place conditioning protocols that reveal both THC rewarding and aversive properties. Absence of microreceptors abolishes THC place preference. Deletion of kappa receptors ablates THC place aversion and furthermore unmasks THC place preference. Thus, an opposing activity of mu- and kappa-opioid receptors in modulating reward pathways forms the basis for the dual euphoric-dysphoric activity of THC.

Psychopharmacology (Berl) 2002 Aug;163(1):111-7

Involvement of the opioid system in the anxiolytic-like effects induced by Delta(9)-tetrahydrocannabinol.

Berrendero F, Maldonado R.

Laboratori de Neurofarmacologia, Facultat de Ciencies de la Salut i de la Vida, Universitat Pompeu Fabra, C/Doctor Aiguader 80, 08003 Barcelona, Spain.

RATIONALE. Recent studies have shown that several pharmacological actions induced by cannabinoids, including antinociception and reward, involve the participation of the endogenous opioid system. OBJECTIVES. The present study was designed to examine the possible involvement of the different opioid receptors in the anxiolytic-like responses induced by Delta(9)-tetrahydrocannabinol (THC). METHODS. The administration of a low dose of THC (0.3 mg/kg) produced clear anxiolytic-like responses in the light-dark box, as previously reported. The effects of the pretreatment with the CB(1) cannabinoid receptor antagonist, SR 141716A (0.5 mg/kg), or the micro -opioid receptor antagonist, beta-funaltrexamine (5 mg/kg), the delta-opioid receptor antagonist, naltrindole (2.5 mg/kg) and the kappa-opioid receptor antagonist, nor-binaltorphimine (2.5 mg/kg) were evaluated on anxiolytic-like responses induced by THC. RESULTS. SR 141716A completely blocked the anxiolytic-like response induced by THC, suggesting that this effect is mediated by CB(1) cannabinoid receptors. The micro -opioid receptor antagonist beta-funaltrexamine and the delta-opioid receptor antagonist naltrindole, but not the kappa-opioid receptor antagonist nor-binaltorphimine, abolished THC anxiolytic-like effects, suggesting an involvement of micro - and delta-opioid receptors in this behavioural response. CONCLUSIONS. These results demonstrate that the endogenous opioid system is involved in the regulation of anxiety-like behaviour by cannabinoids and provide new findings to clarify further the interaction between these two neuronal systems.