Kappa signaling and Dopamine breakthrough

[Neuroprotection]

I have read a study that claimed to identify the link between Kappa opioid receptor activation and suppression of normal Dopamine release, something that can result in dysphoria from Kappa agonists. Apparently Kappa Activation induces P38Mitogen-Activated Protein Kinases as a down stream pathway, and it is this which signals Dopaminergic cells to dramatically reduce their Dopamine output. The Same study also states that inhibition of this Kinase with small molecules can abolish the Dopaminergic suppression caused by Kappa signalling while maintaining all the other affects.
This rases some interesting questions.
1 How could this affect the Salvia experience?
2 Could inhibiting the P38mitogen-activated protein Kinases reduce the psychotic aspects of Kappa agonists?
3 If this works to make the affects of Kappa opioid Agonists more pleasant, or removes dysphoria, could drugs like Salvia/Salvinorin A become addictive.
4 Could such a breakthrough remove some of the supposed benefits of Kappa agonists, that is, is temporary reduction of Dopamine release important for positive long turm effects e.g. anti-addiction or afterglow.
Just for your information, P38MAPK inhibitors have been studied as anti-inflammatory drugs, but I’m not sure if they are still available.

 

[serotonin2A]

It is generally a bad approach to directly target second messengers like p38 MAPK in the brain for therapeutic purposes. MAPK is involved in a multitude of functions other than regulating dopaminergic activity, and all of those functions would be disturbed by MAPK inhibitors.

 

[Neuroprotection]

Interesting reply, do you know what particular functions MAPK inhibition could impair in the brain? And could this cause damage?
Thanks

 

[Cotcha Yankinov]

It is generally a bad approach to directly target second messengers like p38 MAPK in the brain for therapeutic purposes. MAPK is involved in a multitude of functions other than regulating dopaminergic activity, and all of those functions would be disturbed by MAPK inhibitors.

I'm curious what you think of the new target Ephexin 5. Supposedly it is expressed at low levels in normal brains but overexpressed in Alzheimer's disease.

It appears to play an important role in dendritic spine outgrowth and is protective against synapse loss - maybe Ephexin 5 modulation has potential to treat more than just Alzheimer's?

http://www.hopkinsmedicine.org/news...be_new_target_for_treating_alzheimers_disease

https://www.ncbi.nlm.nih.gov/m/pubmed/28185854/

 

[serotonin2A]

Interesting reply, do you know what particular functions MAPK inhibition could impair in the brain? And could this cause damage?
Thanks

This is a fundamental signaling pathway for most neurons. MAPK inhibitors wouldn't cause damage, but certain signaling cascades wouldn't function normally. I am guessing that if MAPK was inhibited sufficiently in the brain that it might produce something like "chemo brain". Indeed, MAPK inhibitors are being developed as chemotherapeutics -- that is one indication where extrene neurological side-effects are tolerated.

MAPK is involved in BDNF signaling. So MAPK inhibitors that enter the brain might blunt the response to BDNF, meaning that they might inhibit synaptic reorganization.