It could even be a weak opioid agonist, but have a second mechanism mediated by NMDA that causes a more profound total effect at reducing pain or producing opiate-like effects.
sekio said:
I have a strong feeling that, like ketamine, MXE's purported "opioid" effects are only present at abnormally high doses and do not contribute to the recreational "flavour" of the drug.
laCster said:
thank you for shinning more light on this topic, sekio; your insight is always appreciated. do you believe sigma-receptor affinity contributes to MXE's recreational effects?
I guess my post just wasn't worth reading was it? Oh no something that was actually backed up with an actual piece of science and not purely here say couldn't possibly be read or appreciated.
I bet the sekio sigma response will blow some minds as well.
Just in case it does, I'll make another comment for people to steal or blow over that isn't just here say.
There is yet to be much definite pharmacological characterization of sigma receptors in humans, so it is hard to say precisely what they do. Sigma 2 receptors are being investigated for cancer treatment. Sigma 1 seem to have gained more steam around the area of cognition, perhaps related to neurite outgrowth and has been well investigated for being involved with the effects of cocaine. Another paper I found says a sigma 1 agonist attenuates the stimulant effects of methamphetamine.
Some other interesting new research on sigma 1 can be found related to NMDA receptors:
Neuroscience. 2011 Mar 17;177:12-22. Epub 2011 Jan 4.
Activation of the sigma receptor 1 suppresses NMDA responses in rat retinal ganglion cells.
Zhang XJ, Liu LL, Jiang SX, Zhong YM, Yang XL.
Source
Institute of Neurobiology, State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yixueyuan Road, Shanghai 200032, PR China.
Abstract
The sigma receptor 1 (σR1) has been shown to modulate the activity of several voltage- and ligand-gated channels. Using patch-clamp techniques in rat retinal slice preparations, we demonstrated that activation of σR1 by SKF10047 (SKF) or PRE-084 suppressed N-methyl-D-aspartate (NMDA) receptor-mediated current responses from both ON and OFF type ganglion cells (GCs), dose-dependently, and the effect could be blocked by the σR1 antagonist BD1047 or the σR antagonist haloperidol. The suppression by SKF of NMDA currents was abolished with pre-incubation of the G protein inhibitor GDP-β-S or the Gi/o activator mastoparan. We further explored the intracellular signaling pathway responsible for the SKF-induced suppression of NMDA responses. Application of either cAMP/the PKA inhibitor Rp-cAMP or cGMP/the PKG inhibitor KT5823 did not change the SKF-induced effect, suggesting the involvement of neither cAMP/PKA nor cGMP/PKG pathway. In contrast, suppression of NMDA responses by SKF was abolished by internal infusion of the phosphatidylinostiol-specific phospholipase C (PLC) inhibitor U73122, but not by the phosphatidylcholine-PLC inhibitor D609. SKF-induced suppression of NMDA responses was dependent on intracellular Ca2+ concentration ([Ca2+]i), as evidenced by the fact that the effect was abolished when [Ca2+]i was buffered with 10 mM BAPTA. The SKF effect was blocked by xestospongin-C/heparin, IP3 receptor antagonists, but unchanged by ryanodine/caffeine, ryanodine receptor modulators. Furthermore, application of protein kinase C inhibitors Bis IV and Gö6976 eliminated the SKF effect. These results suggest that the suppression of NMDA responses of rat retinal GCs caused by the activation of σR1 may be mediated by a distinct [Ca2+]i-dependent PLC-PKC pathway. This effect of SKF could help ameliorate malfunction of GCs caused by excessive stimulation of NMDA receptors under pathological conditions.
Here you will see this group characterized sigma 1 to suppress NMDA receptor activity. It is not unfeasible to think a molecule like MXE, which is very potent and effective at what it does, could have multiple mechanisms at shutting down NMDA activity. It could be an equally, or nearly equally, potent NMDA antagonist and sigma 1 agonist, resulting in a broader and more effective mechanism for NMDA activity suppression than either alone is capable of.
There is some work characterizing ketamine and sigma 1 activity as well, which would further support that MXE has some activity there. The paper below is the only recent publication to appear in this area though.
Eur Neuropsychopharmacol. 2011 Sep 10. [Epub ahead of print]
Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo.
Robson MJ, Elliott M, Seminerio MJ, Matsumoto RR.
Abstract
Ketamine is an NMDA antagonist and dissociative anesthetic that has been shown to display rapid acting and prolonged antidepressant activity in small-scale human clinical trials. Ketamine also binds to σ receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine the involvement of σ receptors in the antidepressant-like actions of ketamine. Competition binding assays were performed to assess the affinity of ketamine for σ(1) and σ(2) receptors. The antidepressant-like effects of ketamine were assessed in vitro using a neurite outgrowth model and PC12 cells, and in vivo using the forced swim test. The σ receptor antagonists, NE-100 and BD1047, were evaluated in conjunction with ketamine in these assays to determine the involvement of σ receptors in the antidepressant-like effects of ketamine. Ketamine bound to both σ(1) and σ(2) receptors with μM affinities. Additionally, ketamine potentiated NGF-induced neurite outgrowth in PC12 cells and this effect was attenuated in the presence of NE-100. Ketamine also displayed antidepressant-like effects in the forced swim test; however, these effects were not attenuated by pretreatment with NE-100 or BD1047. Taken together, these data suggest that σ receptor-mediated neuronal remodeling may contribute to the antidepressant effects of ketamine.
Recognize they use ketamine to displace the sigma antagonists, to show it is a specific sigma 1 or 2 agonist with "uM affinity." Hence the true potency at a sigma 1 agonism, without the presence of an antagonist, is probably in the range of 10-100 nM.
Also recognize sigma receptors are located inside the cell, so ketamine or MXE would also have to pass into the cell first to show this activity. This complicates things quite a bit, and would suggest effects at sigma receptors are probably secondary to primary action at cell surface targets.
I am not sure how the study I posted above gets ketamine to show good activity at sigma receptors then. Either it passes through the neurite passively, or sigma receptors are not always located inside the cell (instead sometimes at the membrane) as many other publications have indicated.