The effects of mitragynine and morphine on schedule-controlled responding and antinociception in rats

Hiranita, Takato; León, Francisco; Felix, Jasmine S.; Restrepo, Luís Fernando; Reeves, Morgan E.; Pennington, Anna E.; Obeng, Samuel; Avery, Bonnie A.; McCurdy, Christopher R.; McMahon, Lance Richard; Wilkerson, Jenny L.

doi:10.1007/s00213-019-05247-7

Cited by 44 publications

(47 citation statements)

References 21 publications

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“…In the present study, the magnitude of the naltrexone-induced shift in the mitragynine dose-effect function could not be calculated because 100 mg/kg of mitragynine disrupted behavior and was lethal in a subset of animals even in the presence of naltrexone. The failure of naltrexone to antagonize the rate-decreasing effects of mitragynine has been reported previously (Hiranita et al, 2019).…”

Section: Discussionmentioning

confidence: 73%

“…Morphine, fentanyl, 7-hydroxymitragynine, and U69,593 produced antinociception, whereas mitragynine, buprenorphine, nalbuphine and SNC 80 did not. Mitragynine was also previously ineffective against acutely applied noxious heat in rats (see also Hiranita et al, 2019). In contrast, mitragynine produced antinociceptive effects in mice (Matsumoto et al, 1996a;1996b;Shamima et al, 2012;Kruegel et al, 2019).…”

Section: Discussionmentioning

confidence: 90%

“…The present study assessed the in vitro and in vivo opioid receptor pharmacology of mitragynine extracted from a kratom product at greater than 98% purity (Hiranita et al, 2019), and 7-hydroxymitragynine synthesized from mitragynine as previously described (Obeng et al, 2020). Binding affinity was assessed through displacement of radioligand binding at human opioid receptor subtypes, and MOR efficacy was assessed with a [ 35 S]GTPγS assay.…”

Section: Introductionmentioning

confidence: 99%

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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

Obeng

Wilkerson

León

et al. 2020

J Pharmacol Exp Ther

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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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

Obeng

Wilkerson

León

et al. 2020

J Pharmacol Exp Ther

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“…However, in preclinical studies we showed that its main alkaloid mitragynine can at high doses have reinforcing effects and induce addiction-like behavior with adverse cognitive effects in rodents ( Yusoff et al., 2016 ; Ismail et al., 2017 ; Hassan et al., 2019 ). These effects are partly mediated by an opiate-like mechanism ( Stolt et al., 2014 ; Yusoff et al., 2017 ; Obeng et al., 2020 ), but may also involve other targets in the brain ( Yusoff et al., 2018 ; Hiranita et al., 2019 ). Nonetheless, mitragynine can also attenuate morphine intake ( Hemby et al., 2019 ) and reduce withdrawal effects in rats ( Hassan et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Kratom instrumentalization for severe pain self-treatment resulting in addiction – A case report of acute and chronic subjective effects

Müller

Hillemacher

Müller

2020

Heliyon

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Background Kratom is a Southeast Asian plant, which is widely used in this region, and making an increasing appearance in Europe and the US. Case report We present the case of a 26-year-old man in Substitol-assisted treatment of excessive Kratom and Tilidin use expressing the wish for a drug-free management of a chronic pain condition. After an accidental calcaneus impression fracture, the patient was suffering from severe chronic pain and anxiety of further accidents. This was managed initially with Tilidin. Resulting from the wish to self-manage the pain condition in a way that permitted continuation of a job, the patient searched for a ‘natural’ treatment alternative obtained from an Internet vendor. He successfully instrumentalized Kratom for 3 years with daily consumption intermixed with occasional Tilidin for pain management. However, the dose of Kratom was increased considerably up to a level of effect reversal, when no analgesic and behaviorally activating effects occurred any more, but only intense drowsiness. The patient was treatment seeking and subsequently detoxified from Kratom and Tilidin. Pain management was shifted to retarded morphine. Conclusion Kratom instrumentalization for pain management might appear to be more problematic for addiction development than when its use is established for other consumption motives.

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“…Several studies proposed the possibility that mitragynine effects were mediated through opioid receptors (29,41,111,112), Hiranita et al (113) however suggested that mitragynine has different pharmacological mechanism as compared to morphine. Its antinociceptive effect is not mediated via opioid receptor since naltrexone which antagonize morphine's effects on schedule-controlled responding and thermal response latency did not alter mitragynine's effects significantly (113). Furthermore, a study by Hemby et al (114) showed that mitragynine is a good candidate for pharmacotherapies, since it reduces morphine intake.…”

Section: Discussionmentioning

confidence: 99%

Mitragynine Attenuates Morphine Withdrawal Effects in Rats—A Comparison With Methadone and Buprenorphine

et al. 2020

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Background: Opiate addiction is a major health problem in many countries. A crucial component of the medical treatment is the management of highly aversive opiate withdrawal signs, which may otherwise lead to resumption of drug taking. In a medication-assisted treatment (MAT), methadone and buprenorphine have been implemented as substitution drugs. Despite MAT effectiveness, there are still limitations and side effects of using methadone and buprenorphine. Thus, other alternative therapies with less side effects, overdosing, and co-morbidities are desired. One of the potential pharmacotherapies may involve kratom's major indole alkaloid, mitragynine, since kratom (Mitragyna speciosa Korth.) preparations have been reported to alleviate opiate withdrawal signs in self-treatment in Malaysian opiate addicts. Methods: Based on the morphine withdrawal model, rats were morphine treated with increasing doses from 10 to 50 mg/kg twice daily over a period of 6 days. The treatment was discontinued on day 7 in order to induce a spontaneous morphine abstinence. The withdrawal signs were measured daily after 24 h of the last morphine administration over a period of 28 abstinence days. In rats that developed withdrawal signs, a drug replacement treatment was given using mitragynine, methadone, or buprenorphine and the global withdrawal score was evaluated. Results: The morphine withdrawal model induced profound withdrawal signs for 16 days. Mitragynine (5-30 mg/kg; i.p.) was able to attenuate acute withdrawal signs in morphine dependent rats. On the other hand, smaller doses of methadone (0.5-2 mg/kg; i.p.) and buprenorphine (0.4-1.6 mg/kg; i.p.) were necessary to mitigate these effects. Conclusions: These data suggest that mitragynine may be a potential drug candidate for opiate withdrawal treatment.

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The effects of mitragynine and morphine on schedule-controlled responding and antinociception in rats

Cited by 44 publications

References 21 publications

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

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

Kratom instrumentalization for severe pain self-treatment resulting in addiction – A case report of acute and chronic subjective effects

Mitragynine Attenuates Morphine Withdrawal Effects in Rats—A Comparison With Methadone and Buprenorphine

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