作者: Mores, Kendall L. ; Ko, Mee Jung ; Uprety, Rajendra ; Cassell, Robert J. ; Majumdar, Susruta ; van Rijn, Richard M. ; Robins, Meridith T. ; Pasternak, Gavril W. ; Gutridge, Anna M.

Background and PurposeMitragyna speciosa, more commonly known as kratom, is a plant that contains opioidergic alkaloids but is unregulated in most countries. Kratom is used in the self‐medication of chronic pain and to reduce illicit and prescription opioid dependence. Kratom may be less dangerous than typical opioids because of the stronger preference of kratom alkaloids to induce receptor interaction with G proteins over β‐arrestin proteins. We hypothesized that kratom (alkaloids) can also reduce alcohol intake.Experimental ApproachWe pharmacologically characterized kratom extracts, kratom alkaloids (mitragynine, 7‐hydroxymitragynine, paynantheine, and speciogynine) and synthetic carfentanil‐amide opioids for their ability to interact with G proteins and β‐arrestin at μ, δ, and κ opioid receptors in vitro. We used C57BL/6 mice to assess to which degree these opioids could reduce alcohol intake and whether they had rewarding properties.Key ResultsKratom alkaloids were strongly G protein‐biased at all three opioid receptors and reduced alcohol intake, but kratom and 7‐hydroxymitragynine were rewarding. Several results indicated a key role for δ opioid receptors, including that the synthetic carfentanil‐amide opioid MP102—a G protein‐biased agonist with modest selectivity for δ opioid receptors—reduced alcohol intake, whereas the G protein‐biased μ opioid agonist TRV130 did not.Conclusion and ImplicationsOur results suggest that kratom extracts can decrease alcohol intake but still carry significant risk upon prolonged use. Development of more δ opioid‐selective synthetic opioids may provide a safer option than kratom to treat alcohol use disorder with fewer side effects.

2019-09-01·Addiction Biology2区 · 医学

Abuse liability and therapeutic potential of the Mitragyna speciosa (kratom) alkaloids mitragynine and 7‐hydroxymitragynine

2区 · 医学

Article

作者: Cutler, Stephen J. ; Hemby, Scott E. ; Leon, Francisco ; McIntosh, Scot ; McCurdy, Christopher R.

AbstractKratom, derived from the plant Mitragyna speciosa, is receiving increased attention as an alternative to traditional opiates and as a replacement therapy for opiate dependence. Mitragynine (MG) and 7‐hydroxymitragynine (7‐HMG) are major psychoactive constituents of kratom. While MG and 7‐HMG share behavioral and analgesic properties with morphine, their reinforcing effects have not been examined to date. 7‐HMG, but not MG, substituted for morphine self‐administration in a dose‐dependent manner in the rat self‐administration paradigm. Following the substitution procedure, re‐assessment of morphine self‐administration revealed a significant increase following 7‐HMG and a significant decrease following MG substitution. In a separate cohort, 7‐HMG, but not MG, engendered and maintained intravenous self‐administration in a dose‐dependent manner. The effects of pretreatment with nalxonaxine (NLXZ), a μ1 opiate receptor antagonist, and naltrindole (NTI), a δ opiate receptor antagonist, on 7‐HMG and morphine self‐administration were also examined. Both NLXZ and NTI reduced 7‐HMG self‐administration, whereas only NLXZ decreased morphine intake. The present results are the first to demonstrate that 7‐HMG is readily self‐administered, and the reinforcing effects of 7‐HMG are mediated in part by μ and δ opiate receptors. In addition, prior exposure to 7‐HMG increased subsequent morphine intake whereas prior exposure to MG decreased morphine intake. The present findings indicate that MG does not have abuse potential and reduces morphine intake, desired characteristics of candidate pharmacotherapies for opiate addiction and withdrawal, whereas 7‐HMG should be considered a kratom constituent with high abuse potential that may also increase the intake of other opiates.

2016-01-01·British Journal of Pharmacology2区 · 医学

β‐Arrestin 2 dependence of δ opioid receptor agonists is correlated with alcohol intake

2区 · 医学

Article

作者: Sansuk, K ; Chiang, T ; van Rijn, R M

Background and Purposeδ Opioid receptor agonists are being developed as potential treatments for depression and alcohol use disorders. This is particularly interesting as depression is frequently co‐morbid with alcohol use disorders. Yet we have previously shown that δ receptor agonists range widely in their ability to modulate alcohol intake; certain δ receptor agonists actually increase alcohol consumption in mice. We propose that variations in β‐arrestin 2 recruitment contribute to the differential behavioural profile of δ receptor agonists.Experimental ApproachWe used three diarylmethylpiperazine‐based non‐peptidic δ receptor selective agonists (SNC80, SNC162 and ARM390) and three structurally diverse δ receptor agonists (TAN‐67, KNT127 and NIH11082). We tested these agonists in cAMP and β‐arrestin 2 recruitment assays and a behavioural assay of alcohol intake in male C57BL/6 mice. We used β‐arrestin 2 knockout mice and a model of depression‐like behaviour to further study the role of β‐arrestin 2 in δ receptor pharmacology.Key ResultsAll six tested δ receptor agonists were full agonists in the cAMP assay but displayed distinct β‐arrestin 2 recruitment efficacy. The efficacy of δ receptor agonists to recruit β‐arrestin 2 positively correlated with their ability to increase alcohol intake (P < 0.01). The effects of the very efficacious recruiter SNC80 on alcohol intake, alcohol place preference and depression‐like behaviour were β‐arrestin 2‐dependent.Conclusions and ImplicationsOur finding that δ receptor agonists that strongly recruit β‐arrestin 2 can increase alcohol intake carries important ramifications for drug development of δ receptor agonists for treatment of alcohol use disorders and depressive disorders. © 2015 The British Pharmacological Society

100 项与 δ opioid receptor modulators(Chinese Academy of Sciences) 相关的药物交易

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