Therapeutic Potential of G‐protein‐Biased Kratom‐Derived and Synthetic Carfentanil‐Amide Opioids for Alcohol Use Disorder

Abstract

Mitragyna speciosa, also known as kratom, is a plant containing opioidergic alkaloids and is currently being used to self‐medicate chronic pain, opioid dependence, and is also used as a heroin substitute. Kratom, though unscheduled, may be less dangerous when compared to prescription opioids due to the preferential interaction of kratom alkaloids with G‐proteins instead of beta‐arrestin proteins. We hypothesized that kratom alkaloids and synthetic opioids with similar biased pharmacology can be used to treat alcohol use disorder. We completed in vitro pharmacological characterization for two kratom strain extracts, four kratom alkaloids (mitragynine, 7‐hydroxymitragynine, paynantheine, and speciogynine), and a series of synthetic carefentanil‐amide opioids by determining their ability to interact selectively with G‐proteins instead of beta‐arrestin at the mu, delta and kappa opioid receptors. In addition, in C57BL/6 mice we assessed if kratom (alkaloids) and opioids were capable of reducing alcohol use and determined if the alkaloids had rewarding properties. We found that kratom alkaloids are strongly biased towards the G‐protein pathway at all three opioid receptors. More specifically, we found the delta opioid receptor plays an important role in the mechanism of action as interpreted from reduced efficacy in knockout mice. MP102, one of the synthesized carfentanilamide opioids, displayed a pharmacological profile similar to the kratom alkaloids but with preference for delta opioid receptors, and also reduced alcohol intake and likewise produced less significant place preference than morphine. Our findings demonstrate that kratom use can decrease alcohol use, but its use still carries substantial risk. The development of further delta‐opioid‐selective synthetic opioids may provide an avenue for alcohol use treatment that does not produce strong rewards.Support or Funding InformationRMvR support: NIH grants AA025368, AA026949, AA026675, DA045897, a NARSAD young investigator award from The Brain and Behavior Research Foundation, the Purdue Institute for Drug Discovery and the Dept. of Med.Chem. and Molecular Pharmacology. SM support: NIH grants DA045884, DA046487, AA026949 and W81XWH‐17‐1‐0256 & start‐up funds from the Center for Clinical Pharmacology in St. Louis. Funded in part through NIH/NCI Cancer Center Support Grant P30. CA008748.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.