Alpha 2-Adrenergic Agonist Question

[King Tryptamine]

Alright so after doing some research in trying to elucidate the mechanism whereby mitragynine / 7-HO-mitragynine in M.speciosa produces a stimulating effect akin to caffeine in low doses. I came across two main subtypes of receptors regarding its pharmacological action. The mu-opioid receptor and the alpha 2-adrenergic receptor, the prior being attributed to the main CNS and peripheral effects it produces in vivo, functioning as an agonist / partial agonist to both receptors.

Looking at other ligands which function as agonists / partial agonists towards the mu-opioid receptor and even the kappa-opioid subtype such as morphine and salvinorin A, respectively. I drew the conclusion that this may not be the family of GPCR's responsible for the stimulant effects kratom produces in low doses.

What about mitragynines agonist action at the alpha-adrenergic recptor? After doing a little reading on the action of agonists on the alpha 2-adrenergic receptor I became a little confused about the resulting effect. E.g. In the case for agonist guanabenz an inhibitory effect is produced resulting in CNS depression. However in the case for agonist norepinephrine a stimulating effect is produced resulting in CNS arousal. Can any you nexus members chime in as to why two agonist of the alpha 2-adrenergic receptor produce contradictory effects in the CNS? Such as is the case for guanabenz and norepinephrine.

P.S. Wasn't exactly sure where to post this question.

 

[corpus callosum]

Guanabenz acts on alpha 2 receptors which are located pre-synaptically on noradrenergic neurones and the effect is to reduce noradrenaline release by these neurones thereby producing sedation (and other effects) ie the "braking effect" on noradrenaline release (and hence stimulation) results in sedation.

Noradrenaline also acts on these same pre-synaptic "braking" receptors but these neurones project far and wide and interact with a number of different neurotransmitter systems, the net effect of which tends to exceed the braking effect seen via the pre-synaptic alpha 2 receptors.

This is a simplified account and several subtypes of the alpha 2 receptor have been found, and some of these are strongly implicated in producing ADHD. Fascinating stuff!

 

[King Tryptamine]

I wasn't expecting to be getting feedback on this one, especially so soon. Anyway would this criteria classify the pre-synaptic alpha 2 complex as an autoreceptor?

Hmm... I wonder if the stimulant aspect of mitragynine / 7-HO-mitragynine stems from its agonist action being more selective towards post-synaptic alpha 2's opposed to pre-synaptic alpha 2's. Oh well guess I'll have to do more research.

Thanks for the clarification Doc

 

[dragonrider]

Isn't that stimulant effect dose dependant as well?

I always thought it had something to do with the fact that mitragyne had a high affinity for delta receptors, and a relatively low affinity for mu receptors, so you just needed more for the sedative effects to kick in.

 

[King Tryptamine]

I think the stimulant effect is dose dependent looking at online documents, have yet to try it.

I think you're right in that the depressant effects become more pronounced with elevated doses. IMO this may possibly be due to the inhibitory opiodergic system becoming more pronounced, hence overriding the excitatory complexes in the CNS inducing a different net effect at these dosages. Stimulant to narcotic in high doses (net inhibition) and narcotic to stimulant with low doses (net excitation). Just an assumption, not declaring this as fact or anything!

 

[muladharma]

I want to follow up with a curiosity of my own.

I have recently experimented with a single dose of 20mg dextromethorphan HBr, and had the surprise of discovering a physical sensation not unfamiliar to me. The sensation is similar as far as I can remember to the T+20m (minutes) and T+1h20m of a 100 microgram LSD or 1P-LSD dose. It is also similar to a physical sensation of smoked DMT. I'd describe it as the feeling one gets when he/she slips on a thin sheet of ice, in the instant of experiencing shock and losing balance and orientation. Also, the feeling when one is drinking water for a long enough time to have to stop gasping for air, the sensation while gasping feels like that.

After researching the receptor affinity spectrum of the compound, I noticed the Adrenergic receptors alpha-1 and alpha-2 affinity. I have yet to try ephedrine or epinephrine/norepinephrine to see what I'd discover, but after drinking an unusual number of two coffees in a row, I noticed a sensation very similar to the dextromethorphan experience.

Please note that the dextromethorphan produced the physical sensation I'm trying to correlate with the adrenergic receptors for a period of about one day, with the sensation being present even after a good night's sleep.

I hope to gain insights into my brain's perception of epinephrine and/or adrenergic activity, to better understand myself.


After a few days of slowly searching and integrating new neurochemical knowledge I found the following papers of relevance:

Cross interaction of dopaminergic and adrenergic systems in neural modulation Cross interaction of dopaminergic and adrenergic systems in neural modulation

https://pubs.acs.org/doi/10.1021/acschemneuro.9b00073 Serotonin Regulation of the Prefrontal Cortex: Cognitive Relevance and the Impact of Developmental Perturbation