Pharmacological Comparison of Mitragynine and 7-Hydroxymitragynine: In Vitro Affinity and Efficacy for<i>μ</i>-Opioid Receptor and Opioid-Like Behavioral Effects in Rats

Obeng, Samuel; Wilkerson, Jenny L.; León, Francisco; Reeves, Morgan E.; Restrepo, Luís Fernando; Gamez-Jimenez, Lea R.; Patel, Avi; Pennington, Anna E.; Taylor, Victoria A.; Ho, Nicholas P.; Braun, Tobias; Fortner, John D.; Crowley, Morgan L.; Williamson, Morgan R.; Pallares, Victoria L.C.; Mottinelli, Marco; Lopera-Londoño, Carolina; McCurdy, Christopher R.; McMahon, Lance Richard; Hiranita, Takato

doi:10.1124/jpet.120.000189

Cited by 63 publications

(63 citation statements)

References 41 publications

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“…While antinociception has been reported for 7-hydroxymitragynine, the weaker μOR affinity alkaloid mitragynine reportedly lacks antinociceptive ability, and has been suggested to act as a μOR antagonist ( Obeng et al, 2021 ); although in the cAMP assay, we previously identified mitragynine as a partial agonist ( Gutridge et al, 2020 ), which is in line with a couple of other reports ( Kruegel et al, 2016 ; Váradi et al, 2016 ). Paynantheine has weaker potency for the μOR than mitragynine in the cAMP assay but is more efficacious ( Gutridge et al, 2020 ), which begged the question whether paynantheine possessed antinociceptive activity.…”

Section: Discussionsupporting

confidence: 90%

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

et al. 2021

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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.

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Section: Discussionsupporting

confidence: 90%

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

et al. 2021

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“…The same behavior was not seen even after the 294 mg/kg MTG dose, indicating that the amount of 7HMG generated as a metabolite of MTG is either insufficient to produce the response or MTG may antagonize the 7HMG-induced Straub tail response. This is supported by in vitro evidence, as MTG antagonized activity of 7HMG at human MOR using a [ 35 S]GTPγS functional assay (Obeng et al, 2021).…”

Section: Discussionsupporting

confidence: 52%

“…The formulation or vehicle was filtered with a 0.2-µm pore size syringe filter (Millex-LG, Sigma Aldrich Co.) prior to administration. The dose ranges and pretreatment times were chosen based on preliminary data and published methods (Tanda 2016, Obeng 2021, Behnood 2020, Obeng 2020, Hiranita 2019. For the pharmacokinetic studies, MTG and 7HMG were prepared by dissolving MTG hydrochloride and 7HMG free base in purified water with 3% (v/v) Tween 80 ® to get a freebase equivalent solution of 16.5 and 5.0 mg/mL, respectively.…”

Section: Methodsmentioning

confidence: 99%

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The Lack of Contribution of 7-Hydroxymitragynine to the Antinociceptive Effects of Mitragynine in Mice: A Pharmacokinetic and Pharmacodynamic Study

et al. 2021

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“…Most notable among these with dose-dependent psychoactive effects are mitragynine (MG) and 7-hydroxymitragynine (7-HMG). Both alkaloids bind to and partially agonize the mu-opioid receptor, producing analgesic, stimulatory, and anxiolytic effects (Kruegel and Grundmann, 2018;Kruegel et al, 2019;Obeng et al, 2021;Todd, et al, 2020). While some of these effects can likely be attributed to mu-opioid receptor activity, others may occur through separate mechanisms (Hiranita et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Kratom Use in the US: Both a Regional Phenomenon and a White Middle-Class Phenomenon? Evidence From NSDUH 2019 and an Online Convenience Sample

Rogers¹,

Smith²,

Strickland³

et al. 2021

Front. Pharmacol.

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Kratom products available in the United States are becoming increasingly diverse both in terms of content and in terms of how they are marketed. Prior survey research indicates that kratom has been primarily used in the US to self-treat anxiety, depression, pain, fatigue, and substance use disorder (SUD) symptoms. Kratom is also well-known for its use as a short- or long-term full opioid agonist substitute. Therefore, use may be greater in regions particularly impacted by addiction to prescription opioids. Use may also be greater in demographic groups targeted by media outlets (such as specific podcasts) in which kratom is touted. Here, we aimed to determine whether lifetime and past-year kratom use were associated with region of residence and with being young, White, post-secondary educated, and employed. To strengthen confidence in our findings, we analyzed data from two sources: our own crowdsourced online convenience sample and the 2019 National Survey on Drug Use and Health (NSDUH). In our sample (N = 2,615), 11.1% reported lifetime and 6.7% reported past-year kratom use, and the odds of kratom use were higher among people who were White, younger, at least high school educated, employed, and above the poverty line, as well as those reporting nonmedical opioid use, past-year SUD, or lifetime SUD treatment; residence was not a significant predictor. In NSDUH data, suburban residence and other demographic factors, concordant with those from the crowdsourced sample, were associated with kratom use. Taken together, the findings support a general “White middle-class suburban” profile of the modal kratom user, but more research is needed to understand it. In the interim, focus should be on our finding that lifetime nonmedical opioid use was associated with an up to five times greater likelihood of past-year kratom use, suggesting that drug-use history may presently be the strongest predictor of kratom use.

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Pharmacological Comparison of Mitragynine and 7-Hydroxymitragynine: In Vitro Affinity and Efficacy forμ-Opioid Receptor and Opioid-Like Behavioral Effects in Rats

Cited by 63 publications

References 41 publications

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

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

The Lack of Contribution of 7-Hydroxymitragynine to the Antinociceptive Effects of Mitragynine in Mice: A Pharmacokinetic and Pharmacodynamic Study

Kratom Use in the US: Both a Regional Phenomenon and a White Middle-Class Phenomenon? Evidence From NSDUH 2019 and an Online Convenience Sample

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