Opioid receptors mediate the acquisition, but not the expression of mitragynine-induced conditioned place preference in rats

Kratom, 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.

show abstract

“…; Yusoff et al . ) and both MG and 7‐HMG generalize to the discriminative stimulus effects of morphine (Harun et al . ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

View full text Add to dashboard Cite

show abstract

“…; Yusoff et al . ). Impaired cognitive functions in rodents given with MG were also reported (Yusoff et al .…”

Section: Introductionmentioning

confidence: 97%

Rate and extent of mitragynine and 7‐hydroxymitragynine blood–brain barrier transport and their intra‐brain distribution: the missing link in pharmacodynamic studies

et al. 2018

View full text Add to dashboard Cite

Mitragyna speciosa is reported to be beneficial for the management of chronic pain and opioid withdrawal in the evolving opioid epidemic. Data on the blood-brain barrier (BBB) transport of mitragynine and 7-hydroxymitragynine, the active compounds of the plant, are still lacking and inconclusive. Here, we present for the first time the rate and the extent of mitragynine and 7-hydroxymitragynine transport across the BBB, with an investigation of their post-BBB intra-brain distribution. We utilized an in vitro BBB model to study the rate of BBB permeation of the compounds and their interaction with efflux transporter P-glycoprotein (P-gp). Mitragynine showed higher apical-to-basolateral (A-B, i.e. blood-to-brain side) permeability than 7-hydroxymitragynine. 7-Hydroxymitragynine showed a tendency to efflux, with efflux ratio (B-A/A-B) of 1.39. Both were found to inhibit the P-gp and are also subject to efflux by the P-gp. Assessment of the extent of BBB transport in vivo in rats from unbound brain to plasma concentration ratios (K ) revealed extensive efflux of both compounds, with less than 10 percent of unbound mitragynine and 7-hydroxymitragynine in plasma crossing the BBB. By contrast, the extent of intra-brain distribution was significantly different, with mitragynine having 18-fold higher brain tissue uptake in brain slice assay compared with 7-hydroxymitragynine. Mitragynine showed a moderate capacity to accumulate inside brain parenchymal cells, while 7-hydroxymitragynine showed restricted cellular barrier transport. The presented findings from this systematic investigation of brain pharmacokinetics of mitragynine and 7-hydroxymitragynine are essential for design and interpretation of in vivo experiments aiming to establish exposure-response relationship.

show abstract

“…The alkaloid content in the leaves varies, depending on geographical location and season of harvest ( 55 ). Mitragynine and 7-hydroxymitragynine are the principal psychoactive constituents of M. speciosa and were shown to induce morphine-like effects in animal models ( 31 , 55 , 56 ). The synthesis of the mitragynine was reported by Takayama et al ( 57 ) and later by Ma and colleagues ( 58 , 59 ).…”

Section: Kratom and Mitragyninementioning

confidence: 99%

“…Mitragynine shows the highest affinity to κ-opioid receptors followed by μ- and δ-opioid receptors ( 68 ). It acts as a receptor agonist at μ-opioid receptors and possibly as an antagonist at κ-opioid receptors ( 56 , 69 – 71 ). At cellular level, mitragynine blocks neuronal Ca 2+ channels ( 72 ).…”

Section: Kratom and Mitragyninementioning

confidence: 99%

See 1 more Smart Citation

Novel Psychoactive Substances—Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs

et al. 2017

Self Cite

View full text Add to dashboard Cite

A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. These drugs change the mental state and/or the behavioral performance of an individual and can be instrumentalized for various purposes. After the emergence of a novel psychoactive substance (NPS) and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. With these measures, however, a drug does not disappear, but frequently continues to be used, which eventually allows an even better estimate of the drug's properties. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. They include mitragynine ("Kratom"), synthetic cannabinoids (e.g., "Spice"), dimethyltryptamine and novel serotonergic hallucinogens, the cathinones mephedrone and methylone, ketamine and novel dissociative drugs, γ-hydroxybutyrate, γ-butyrolactone, and 1,4-butanediol. This review shows not only emerging harm potentials but also some potential medical applications.

show abstract

Opioid receptors mediate the acquisition, but not the expression of mitragynine-induced conditioned place preference in rats

Cited by 46 publications

References 32 publications

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

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

Rate and extent of mitragynine and 7‐hydroxymitragynine blood–brain barrier transport and their intra‐brain distribution: the missing link in pharmacodynamic studies

Novel Psychoactive Substances—Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs

Contact Info

Product

Resources

About