Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder

Abstract

Background and Purpose:Mitragyna speciosa extract and kratom alkaloids decrease alcohol consumption in mice at least in part through actions at the δ-opioid receptor (δOR). However, the most potent opioidergic kratom alkaloid, 7-hydroxymitragynine, exhibits rewarding properties and hyperlocomotion presumably due to preferred affinity for the mu opioid receptor (µOR). We hypothesized that opioidergic kratom alkaloids like paynantheine and speciogynine with reduced µOR potency could provide a starting point for developing opioids with an improved therapeutic window to treat alcohol use disorder.Experimental Approach: We characterized paynantheine, speciociliatine, and four novel kratom-derived analogs for their ability to bind and activate δOR, µOR, and κOR. Select opioids were assessed in behavioral assays in male C57BL/6N WT and δOR knockout mice.Key Results: Paynantheine (10 mg∙kg−1, i.p.) produced aversion in a limited conditioned place preference (CPP) paradigm but did not produce CPP with additional conditioning sessions. Paynantheine did not produce robust antinociception but did block morphine-induced antinociception and hyperlocomotion. Yet, at 10 and 30 mg∙kg−1 doses (i.p.), paynantheine did not counteract morphine CPP. 7-hydroxypaynantheine and 7-hydroxyspeciogynine displayed potency at δOR but limited µOR potency relative to 7-hydroxymitragynine in vitro, and dose-dependently decreased voluntary alcohol consumption in WT but not δOR in KO mice. 7-hydroxyspeciogynine has a maximally tolerated dose of at least 10 mg∙kg−1 (s.c.) at which it did not produce significant CPP neither alter general locomotion nor induce noticeable seizures.Conclusion and Implications: Derivatizing kratom alkaloids with the goal of enhancing δOR potency and reducing off-target effects could provide a pathway to develop novel lead compounds to treat alcohol use disorder with an improved therapeutic window.

Kratom (Mitragyna speciosa) Validation: Quantitative Analysis of Indole and Oxindole Alkaloids Reveals Chemotypes of Plants and Products

“…However, a recent analysis by Buckhalter et al demonstrated that "Rifat" kratom (purchased from the same supplier as K55 and K59) does exhibit antidepressant-like and analgesic effects [43]. This activity may be from the two major constituents, 13 and 3-isoajmalicine, or may be attributed to metabolism products, as has been shown with 7-hydroxyspeciogynine [44] and 9-O-desmethylspeciogynine (i.e., gambirine) [45]. Further experiments would be needed to verify any predictions of biological activity based on differences in alkaloid content.…”

Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors

“…The endogenous agonists for the δOR are pentapeptide enkephalins, particularly Leu 5 -enkephalin, but other peptides that originate from plants and other species, like frogs can also bind and activate the δOR [ 1 , 2 ]. Similar to the µ opioid receptor (µOR), which is activated by small molecules from natural products like opium and kratom and fully synthetic small molecules like fentanyl, the δOR can be activated by a variety of naturally occurring and (semi-) synthetic small molecules [ 3 , 4 , 5 , 6 ].…”

“…Front and center have been the ability of δOR selective agonists to reduce chronic pain, be it inflammatory, neuropathic, or migraine [ 7 ]. δOR agonists have shown promise in preventing cardiac and cerebral ischemia [ 8 ], as a potential treatment for neurodegenerative diseases [ 9 , 10 , 11 , 12 , 13 ], and both δOR agonists and antagonists have been proposed as mechanisms for the treatment of alcohol use disorder [ 5 , 14 , 15 , 16 ]. Outside the central nervous system, δOR antagonism and positive allosteric modulation of δOR has been proposed as a treatment for gastrointestinal motility disorders, such as irritable bowel syndrome [ 17 , 18 ].…”

Exploration of beta-arrestin isoform signaling pathways in delta opioid receptor agonist-induced convulsions

“…The δ-opioid receptor (δOR) is a G-protein coupled receptor (GPCR) within the opioid family that has been considered as therapeutic target for the treatment of migraine, chronic pain, anxiety, and major depressive disorder ( Jutkiewicz, 2006 ; Perrine et al, 2006 ; Pradhan et al, 2011 ; Pradhan et al, 2014 ; Gendron et al, 2016 ; Cahill et al, 2022 ). δOR agonists have also been proposed as promising treatments for alcohol use disorder, ischemia, and stroke ( Schultz et al, 1997 ; Karck et al, 2001 ; Alongkronrusmee et al, 2018 ; Grant Liska et al, 2018 ; Sheng et al, 2018 ); particularly as δOR agonists generally display negligible abuse potential ( Van Rijn et al, 2012 ; Hudzik et al, 2014 ; Conibear et al, 2020 ; Gutridge et al, 2021 ) and thus, would be safer alternatives relative to µ-opioid receptor drugs. Yet, in contrast to the µ-opioid and κ-opioid receptor, no δOR selective compounds have been approved for clinical use.…”

“…The ability of SNC80 to induce seizures is absent in δOR knockout mice, indicating an on-target effect ( Broom et al, 2002b ; Chung et al, 2015 ). Yet, multiple δOR selective agonists have been designed and characterized to specifically lack this seizurogenic effect ( Saitoh et al, 2011 ; Saitoh et al, 2018 ; Conibear et al, 2020 ; Fossler et al, 2020 ; Gutridge et al, 2021 ). These findings hint at a concept of biased signaling, where a particular ligand activates a subset of signal-transduction pathways thereby promoting or avoiding specific cellular signaling and associated physiological consequences.…”