The sigma receptors are really confusing, they've been known for around 30 years now yet little is known about what they do at all (at least to my knowledge, and
wikipedia says the same).
That section in White's nice DXM FAQ about sigma seems to still apply to a good part. (The whole FAQ is really worth to read if you're interested in dissociatives, mostly the chapters 5 and 8-10- especially the description of the 'plateaus' applies surprisingly well also to MXE)
This is why I'm very interested in them and memantine's sigmaergic activity ... if sigma agonism is stimulating, anti depressive (see opipramol for example, it did nothing for me but works for others, or fluvoxamine) - DXM seems not to be a direct dopaminergic as initially thought but rather to exhibit this activity through sigma1 receptors, with the sigma2 ones possibly being responsible for that 'robo walk' wobbly motor impairment above a certain dosage - which, afaik, is somewhat unique to DXM as MXE / Ketamine do not share this thing, walking becomes somewhat difficult when being too dissociated, but not wobbly.
Then antagonizing sigma would be contra productive. But it seems wikipedia is wrong in this case, as they don't even mention a source for their claim that memantine is a sigma antagonist and as
serotonin2A pointed out (thanks!) it seems to be a weak/moderate agonist. (Edit: Updated wikipedia & added 3-MeO-PCP as well .. finally my first wiki contribution
)
Sigma agonism can also lead to convulsions and psychosis possibly if activated too strong and/or for too long. I think it's rather about the potency.
Their activation could cause downstream anticholinergic activity (explaining some of the dissociative's & opiate's delirant effects in higher dosages).
And somewhat antagonism can lead to the same changes as agonism (or has this been relativized)?
Remarkable is that the old, nasty haloperidol potently & irreversibly* inactivates sigma1 receptors and was shown to cause lasting changes in hours. Probably this has only been observed in rodents as usual, but it could well explain some of the horrible side effects haloperidol has. (And it is a
dopamine inverse agonist!! Ouch. Maybe the only one used in practice?)
*(that is, until they are renewed... some days to weeks, like with the irreversible MAOIs probably)
Cotcha, do you have a source mentioning the affinities of MXE to sigma1/2 (and possibly other receptors)? Would be very interesting to know!
Behavioral reactions to σ–agonists are rather heterogeneous: some individuals find σ–receptor agonists euphoric with significant anti-depressive effects. Other individuals, however, experience dysphoria and often report feelings of malaise or anxiety.
<--- glutamate (or excitatory transmission) modulation once more!?
