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What do the sigma opioid receptors do when agonized?

Sigma-1 agonists have an antitussive effect and also have some potential as antidepressants: http://www.ncbi.nlm.nih.gov/pubmed/11504830 .

Sigma-2 agonists probably don't have much CNS effects but they have been shown to kill tumor cells, which gives them potential as chemotherapy meds for cancer: http://www.ncbi.nlm.nih.gov/pubmed/11782394 .

Many drugs like PCP, cocaine or DMT bind to sigma receptors, but it doesn't seem to have a major part in their psychoactive mechanism of action.
 
polymath said:
Sigma-1 agonists have an antitussive effect and also have some potential as antidepressants: http://www.ncbi.nlm.nih.gov/pubmed/11504830 .

Sigma-2 agonists probably don't have much CNS effects but they have been shown to kill tumor cells, which gives them potential as chemotherapy meds for cancer: http://www.ncbi.nlm.nih.gov/pubmed/11782394 .

Many drugs like PCP, cocaine or DMT bind to sigma receptors, but it doesn't seem to have a major part in their psychoactive mechanism of action.
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I do remember reading on one site that sigma opioid agonism was a small but "there" part of cocaine's addictiveness.
 
Can it be traced to neurotransmitters or the like though? Is its being agonized associated with a particular state, feeling, or set of feelings?
 
Ho-Chi-Minh said:
Can it be traced to neurotransmitters or the like though? Is its being agonized associated with a particular state, feeling, or set of feelings?
Click to expand...

That's what I was asking. How does it affect neurotransmission? Like, for example, how 5-HT2c antagonism disinhibits dopamine and NE release.
 
The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmatic reticulum (ER) that modulates calcium signaling through the IP3 receptor.
Click to expand...

These aren't g-protein coupled receptors, by the way.
 
well the sigma-1 receptor's endogenous ligand is Dimethyltryptamine (DMT) a naturally occurring tryptamine psychadellic in the brain (correct me if im wrong) is hypothesized to be responsible for part of the process of dreaming in humans

I know from experience abusing dxm that there are two (or more kinds of highs)
when you drink dxm cough syrup and split your dose in 3 or 4 and consume every 30-45 minutes
you allow the metabolization of dxo (which has a 10 fold higher nmda antagonism nm)
and provides a very dissociative (pcp/ketamine-esk) trip

whereas if the dxm is consumed all at once it has limited dxo metabolisim and is more hallucinogenic than dissociative due to having around 7,000nm nmda affinity instead of around 700-720nm (dxo)

dxm is also a more potent Sigma-1 agonist than dxo
and is more psychadellic in nature (both from research and 1st hand experience)

so its possible that the sigma-1 is mediating the extra hallucinogenic activity

i believe this is the source for sigma-1 mediated amphetamine psychosis
if not its still a good read due to in-depth dxm mechanism explanation and i believe it touches on the sigma receptor as well

also (new computer dont have all my sources saved)
sigma-1 is hypothesized to be responsible for the bulk of amphetamine psychosis

if you think about it what are the drugs that agonize sigma-1
+phencyclidine
+amphetamine/methamphetamine
+cocaine
+dextromethorphan
all know drugs that cause marked psychosis

erowid page for sigma-1 mediating amphetamine psychosis

http://www.erowid.org/chemicals/dxm/faq/dxm_neuropharm.shtml
"Sigma receptors seem to be involved in psychotomimetic (literally "psychosis-like") effects from schizophrenia and drugs (46-49). Amphetamine psychosis, a temporary condition resulting from heavy use of psychostimulants, may be due in part to sigma1 activity (80,125). Sigma, and in particular sigma1, receptors may be altered by schizophrenia. An alternative possibility which is being studied is that some sort of chemical - produced by the body itself, or by a virus or other foreign agent - causes prolonged activation of sigma receptors, and this is one of the causes for schizophrenia (47,49). Many neuroleptics, including some of the atypical ones, are sigma antagonists (47,260). Some antidepressants are also sigma antagonists, and all eventually reduce sigma binding (260). Methamphetamine increases sigma binding (211)."

article on ndma and sigma modulation via Dxm/Dxo (also helpful as it talks about sigma)
http://www.braintechllc.com/Dextromethorphan.aspx
 
Last edited:
allthegoodjwh's said:
well the sigma-1 receptor's endogenous ligand is Dimethyltryptamine (DMT) a naturally occurring tryptamine psychadellic in the brain (correct me if im wrong) is hypothesized to be responsible for part of the process of dreaming in humans

I know from experience abusing dxm that there are two (or more kinds of highs)
when you drink dxm cough syrup and split your dose in 3 or 4 and consume every 30-45 minutes
you allow the metabolization of dxo (which has a 10 fold higher nmda antagonism nm)
and provides a very dissociative (pcp/ketamine-esk) trip

whereas if the dxm is consumed all at once it has limited dxo metabolisim and is more hallucinogenic than dissociative due to having around 7,000nm nmda affinity instead of around 700-720nm (dxo)

dxm is also a more potent Sigma-1 agonist than dxo
and is more psychadellic in nature (both from research and 1st hand experience)

so its possible that the sigma-1 is mediating the extra hallucinogenic activity

i believe this is the source for sigma-1 mediated amphetamine psychosis
if not its still a good read due to in-depth dxm mechanism explanation and i believe it touches on the sigma receptor as well

also (new computer dont have all my sources saved)
sigma-1 is hypothesized to be responsible for the bulk of amphetamine psychosis

if you think about it what are the drugs that agonize sigma-1
+phencyclidine
+amphetamine/methamphetamine
+cocaine
+dextromethorphan
all know drugs that cause marked psychosis

erowid page for sigma-1 mediating amphetamine psychosis

http://www.erowid.org/chemicals/dxm/faq/dxm_neuropharm.shtml
"Sigma receptors seem to be involved in psychotomimetic (literally "psychosis-like") effects from schizophrenia and drugs (46-49). Amphetamine psychosis, a temporary condition resulting from heavy use of psychostimulants, may be due in part to sigma1 activity (80,125). Sigma, and in particular sigma1, receptors may be altered by schizophrenia. An alternative possibility which is being studied is that some sort of chemical - produced by the body itself, or by a virus or other foreign agent - causes prolonged activation of sigma receptors, and this is one of the causes for schizophrenia (47,49). Many neuroleptics, including some of the atypical ones, are sigma antagonists (47,260). Some antidepressants are also sigma antagonists, and all eventually reduce sigma binding (260). Methamphetamine increases sigma binding (211)."

article on ndma and sigma modulation via Dxm/Dxo (also helpful as it talks about sigma)
http://www.braintechllc.com/Dextromethorphan.aspx
Click to expand...

I thought psychosis was mainly caused by overactivation of d2 and 5-ht2a?
 
I was once prescribed noscapine, a pretty weak cough suppressant which acts primarily through activation of sigma receptors. In higher dosages, it causes a very weak "high". Not psychedelic, no euphoria but not completely unpleasant either. It just makes you a little slow/dumb, maybe a bit dreamy.

I don't think anyone would use this recreationally on its own. But I could imagine that sigma agonism makes a small contribution to the high of cocaine or ketamine/pcp/dxm or even poppy seed tea (opium contains significant amounts of noscapine).
 
I think officially its thought to be mediated through D2 and to a lesser extent 5-HT2A as well as various other dopamine and serotonin sites and various adrenergic receptors. Probably to answer this one we could find out whether clinical psychosis is closer to being under the strong influence of a psychedelic or a stimulant. But now we know sigma receptors can play a role too. Thanks for that information allthegood. Its interesting that DMT is the endogenous ligand.

So some antidepressants decrease sigma activity, while sigma agonism is being hypothesized as a novel antidepressant mechanism. Hmm.
 
well jackies baby
that is true those are the two main receptors believed to cause psychosis D2 and 5ht-2a Mainly D2 as it is a more delusional schizophrenia-esk feeling while 5ht-2a has hallucinations that are more "otta there" and are more readily identified as a hallucination while D2 can border on the anticholingeric trip side where after going on an adderall IR binge i began taking orders for people that were not there and dropping food out of the window into imaginary "cars" i mean i was doing about 200mg IR over 36 hours so my D2 receptor was heavily agonized

but studys are now showing sigma-1 can be responsible for the psychosis of some drugs especially amphetamine and dextromethorphan
i mean its endogenous ligand is DMT probably (imo) the most powerful psychadellic out there
its gotta have some hallucinogenic properties either itself or downstream activation of receptors
how likely is it that sigma-1 causes downstream agonization of D2 5-ht2a or both?
i belive it causes downstream agonization of "classical psychosis inducing nueroreceptors:
ORRR it has a novel method of action in inducing hallucinations independent of said nueroreceptors
its a poorly researched receptor, but i assumes some one here will know enough to explain this fully
 
DMT as a ligand for sigma-1 still has some debate surrounding it - DMT is not seen in levels large enough to activate sigma-1 in vivo. And other things like neurosteroids also bind to the receptor.
 
hmmmmm sekio that is interesting that you mentioned that, ill have to check my source before i continue mentioning DMT sigma-1 ligand references because one thing i hate is to unknowingly transmit inaccurate info, so yeah. i know the source on sigma-1 being a novel cause of psychosis (especially amphetamine mediated) is of a reliable nature as its erowid related i belive idk i posted it in an airport before a flight and cant remember what went where lol
 
allthegoodjwh's said:
hmmmmm sekio that is interesting that you mentioned that, ill have to check my source before i continue mentioning DMT sigma-1 ligand references because one thing i hate is to unknowingly transmit inaccurate info, so yeah. i know the source on sigma-1 being a novel cause of psychosis (especially amphetamine mediated) is of a reliable nature as its erowid related i belive idk i posted it in an airport before a flight and cant remember what went where lol
Click to expand...

Isn't DMT (mainly) just a 5-HT receptor (mainly 5-HT2a and 5-HT1a) agonist like most other psychedelics? According to wikipedia, it was hypothesized that DMT was the endogenous sigma opioid agonist, but "Under these conditions, notions of receptor selectivity are moot, and it seems probable that most of the receptors identified as targets for DMT (see above) participate in producing its psychedelic effects.".
 
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