KAPPA-OPIATE-ANHEDONIA RESEARCH 2018
- To reverse Kappa or K-Opioid (Salvia, Fetanyl, Salvinorin A, Herbal) induced Anhedonia and / or Dysphoria - you would have to do the following.
- Take MEGA-DOSES of Amentoflavone (AmentoMax) - probably 6 capsules per day. (See Study Here) (See Published Chart on Amentoflavone Binding to Human Kappa-Opioid-Receptors)
- Take EGB-761 (Ginkgo Biloba Max) and 3 tablets twice per day or AT LEAST 120 MG twice a day for a Grand Total of 240 MG Per day.
- Take Forskolin Extract based on the Research below and a cAMP-PDE Inhibitor (Butea Superba Extract or the Drug Dypiridamole/Persantine) to reverse cAMP reducing effects of Opiates.
*This can be seen as an effect ANTIDOTE to Anhedonia although the preferable Method is a 'TRUE' opiate antidote (Naloxone for Overdose but Naltrexone for post Opiate or daily use) - though you can use these *IN ADDITION* certainly.
*CORE RESEARCH*
Cyclic Adenosine Mono Phosphate (cAMP) and Kappa-Opioid-Interactions to Create A "Keep Going" Cycle of Withdrawal and Dependence and Dysphoria/Anhedonia.
It appears the Kappa-Opioid-Receptor negatively modulates specific aspects of the cAMP cycle and thus they may uniquely be selective in that it is primarily Mesolimbic projections that get inhibited.
So Kappa-antagonism may actually be necessary for many people with Anhedonia. Also if something like "Amisulpride" or Amphetamine or both doesn't work for ones Anhedonia - then its a SURE BET that Kappa and natural dynorphin production is way out of control! I've yet to meet maybe only 2 people who don't respond to Amisulpride AND Amphetamine. Another 61 people I talked to all Agree its beyond-beyond Euphoria. :-)
Kappa-Opioid-Ligand-cAMP Study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1403760/
The Role of the Dynorphin/Kappa-opioid Receptor System and CREB in the Compulsive Behaviors Associated with Extended Access to Methamphetamine: https://escholarship.org/uc/item/38q9k9zq
J Pharmacol Exp Ther. 2002 May;301(2):599-604.
Inhibition of cAMP accumulation by kappa-receptor activation in isolated iris-ciliary bodies: role of phosphodiesterase and protein kinase C.: https://www.ncbi.nlm.nih.gov/pubmed/11961062
Lastly, Kappa-Opioid-Induced Anhedonia may also be mediated by INHIBITION of Serotonin uptake and thus enhancement of Brain Serotonin like being on an SSRI-Antidepressant!
Neuropharmacology. 2017 Feb;113(Pt A):281-292. doi: 10.1016/j.neuropharm.2016.10.011. Epub 2016 Oct 12.
Modulation of serotonin transporter function by kappa-opioid receptor ligands.Sundaramurthy S1, Annamalai B2, Samuvel DJ3, Shippenberg TS4, Jayanthi LD1, Ramamoorthy S5.
Kappa opioid receptor (KOR) agonists Produce dysphoria and psychotomimesis. While KOR agonists produce pro-depressant-like effects, KOR antagonists produce anti-depressant-like effects in rodent models. The cellular mechanisms and downstream effector(s) by which KOR ligands produce these effects are not clear. KOR agonists modulate serotonin (5-HT) transmission in the brain regions implicated in mood and motivation regulation. Presynaptic serotonin transporter (SERT) activity is critical in the modulation of synaptic 5-HT and, subsequently, in mood disorders. Detailing the molecular events of KOR-linked Sert regulation is important for examining the postulated role of this protein in mood disorders. In this study, we used heterologous expression systems and native tissue preparations to determine the cellular signaling cascades linked to KOR-mediated SERT regulation. KOR agonists U69,593 and U50,488 produced a time and concentration dependent KOR antagonist-reversible decrease in SERT function. KOR-mediated functional down-regulation of SERT is sensitive to CaMKII and Akt inhibition. The U69,593-evoked decrease in SERT activity is associated with a decreased transport Vmax, reduced SERT cell surface expression, and increased SERT phosphorylation. Furthermore, KOR activation enhanced SERT internalization and decreased SERT delivery to the membrane. These data demonstrate that KOR activation decreases 5-HT uptake by altering SERT trafficking mechanisms and phosphorylation status to reduce the functional availability of surface SERT.
KEYWORDS:
Clearance; Kappa opioid receptor; Phosphorylation; Serotonin; Serotonin transporter; Trafficking.
PMID: 27743931 PMCID: PMC5148672 DOI: 10.1016/j.neuropharm.2016.10.011
