Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid Withdrawal

Wilson, Lisa; Chakraborty, Soumen; Eans, Shainnel O.; Cirino, Thomas J.; Stacy, Heather M.; Simons, Chloe A.; Uprety, Rajendra; Majumdar, Susruta; McLaughlin, Jay P.

doi:10.1007/s10571-020-01034-7

Cited by 43 publications

(60 citation statements)

References 72 publications

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“…A more recent study by Kliewer et al [93] describes the effects of opioids administration in genetically modified mice, expressing modified μ-OR preventing phosphorylation and binding of β-arr2 (11S/T-A μ-OR knock-in mice). The obtained data indicate that, when μ-OR were unable to Used as opium substitute by Asian and reported to decrease withdrawal symptoms in humans [89][90][91][92] Attenuation of withdrawal symptoms in morphinedependent mice [69] Reported to reduce craving by online surveyed [91] Attenuation of reinforcing properties of heroin [75] and morphine [74] PZM21…”

Section: Re-evaluation Of the Role Of β-Arr2 In Mediating Of Opioid Side Effectsmentioning

confidence: 96%

Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors

Kudla

Przewłocki

2021

Pharmacol. Rep

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Opioid analgesics remain a gold standard for the treatment of moderate to severe pain. However, their clinical utility is seriously limited by a range of adverse effects. Among them, their high-addictive potential appears as very important, especially in the context of the opioid epidemic. Therefore, the development of safer opioid analgesics with low abuse potential appears as a challenging problem for opioid research. Among the last few decades, different approaches to the discovery of novel opioid drugs have been assessed. One of the most promising is the development of G protein-biased opioid agonists, which can activate only selected intracellular signaling pathways. To date, discoveries of several biased agonists acting via μ-opioid receptor were reported. According to the experimental data, such ligands may be devoid of at least some of the opioid side effects, such as respiratory depression or constipation. Nevertheless, most data regarding the addictive properties of biased μ-opioid receptor agonists are inconsistent. A global problem connected with opioid abuse also requires the search for effective pharmacotherapy for opioid addiction, which is another potential application of biased compounds. This review discusses the state-of-the-art on addictive properties of G protein-biased μ-opioid receptor agonists as well as we analyze whether these compounds can diminish any symptoms of opioid addiction. Finally, we provide a critical view on recent data connected with biased signaling and its implications to in vivo manifestations of addiction. Graphic abstract

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Section: Re-evaluation Of the Role Of β-Arr2 In Mediating Of Opioid Side Effectsmentioning

confidence: 96%

Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors

Kudla

Przewłocki

2021

Pharmacol. Rep

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“…Opioid-induced hyperalgesia. (DeWire, et al, 2013) (Gillis, Gondin, et al, 2020) (Mori, et al, 2021) (Altarifi, et al, 2017 (Manglik, et al, 2016) (Kudla, et al, 2019) (Gillis, Gondin, et al, 2020) (Hill, et al, 2018) (Manglik, et al, 2016) (Kudla, et al, 2019) (Varadi, et al, 2016) (Varadi, et al, 2016) (Wilson, et al, 2021) (Grim, et al, 2020;Schmid, et al, 2017) (Gillis, Gondin, et al, 2020) (Varadi, et al, 2016) (Wilson, et al, 2021) (Wilson, et al, 2021) (Wilson, et al, 2021) (Wilson, et al, 2021) (Wilson, et al, 2021) (Wilson, et al, 2021) (Wilson, et al, 2021) BRET, GTPgS binding (Faouzi, et al, 2020)…”

Section: -Concluding Remarksmentioning

confidence: 99%

Experimental considerations for the assessment of in vivo and in vitro opioid pharmacology

Hill

Canals

2022

Pharmacology & Therapeutics

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Morphine and other mu-opioid receptor (MOR) agonists remain the mainstay treatment of acute and prolonged pain states worldwide. The major limiting factor for continued use of these current opioids is the high incidence of side effects that result in loss of life and loss of quality of life. The development of novel opioids bereft, or much less potent, at inducing these side effects remains an intensive area of research, with multiple pharmacological strategies being explored. However, as with many G protein-coupled receptors (GPCRs), translation of promising candidates from in vitro characterisation to successful clinical candidates still represents a major challenge and attrition point. This review summarises the preclinical animal models used to evaluate the key opioid-induced behaviours of antinociception, respiratory depression, constipation and opioid-induced hyperalgesia and tolerance.We highlight the influence of distinct variables in the experimental protocols, as well as the potential implications for differences in receptor reserve in each system. Finally, we discuss how methods to assess opioid action in vivo and in vitro relate to each other in the context of bridging the translational gap in opioid drug discovery.

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“…In South-East Asia kratom is used to alleviate muscle aches, and sometimes to heal wounds and cure worm infections, while some users support they assume it to increase resistance to fatigue and to stimulate sexuality (46). Indeed, mitragynine and kratom alkaloids are likely to be associated with "dependence" signs and symptoms which are less severe than those usually associated to opiates and they may be used to alleviate classical opiate withdrawal (47,48). This is not surprising, since they act as agonists on opioid mu receptors.…”

Section: Introductionmentioning

confidence: 99%

Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant

Vento

Persis²,

Filippis³

et al. 2021

Front. Psychiatry

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Kratom or Mitragyna speciosa (Korth.) is an evergreen tree of the coffee family native to South-East Asia and Australasia. It is used by locals recreationally to induce stimulant and sedative effects and medically to soothe pain and opiate withdrawal. Its leaves are smoked, chewed, or infused, or ground to yield powders or extracts for use as liquids. It contains more than 40 alkaloids; among these, mitragynine and 7-hydroxymitragynine are endowed with variable mu, delta, and kappa opioid stimulating properties (with 7-hydroxymitragynine having a more balanced affinity), rhynchophylline, which is a non-competitive NMDA glutamate receptor antagonist, but is present in negligible quantities, and raubasine, which inhibits α1-adrenceptors preferentially over α2-adrenceptors, while the latter are bound by 7-hydroxymitragynine, while mitragynine counters 5-HT2A receptors. This complexity of neurochemical mechanisms may account for kratom's sedative-analgesic and stimulant effects. It is commonly held that kratom at low doses is stimulant and at higher doses sedative, but no cut-off has been possible to define. Long-term use of kratom may produce physical and psychological effects that are very similar to its withdrawal syndrome, that is, anxiety, irritability, mood, eating, and sleep disorders, other than physical symptoms resembling opiate withdrawal. Kratom's regulatory status varies across countries; in Italy, both mitragynine and the entire tree and its parts are included among regulated substances. We describe the case of a patient who developed anxiety and dysphoric mood and insomnia while using kratom, with these symptoms persisting after withdrawal. He did not respond to a variety of antidepressant combinations and tramadol for various months, and responded after 1 month of clomipramine. Well-being persisted after discontinuing tramadol.

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Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid Withdrawal

Cited by 43 publications

References 72 publications

Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors

Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors

Experimental considerations for the assessment of in vivo and in vitro opioid pharmacology

Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant

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