µ-Opioid receptor activation by tramadol and O-desmethyltramadol (M1)

@article{Minami2014OpioidRA,
  title={µ-Opioid receptor activation by tramadol and O-desmethyltramadol (M1)
},
  author={Kouichiro Minami and Yuka Sudo and Kanako Miyano and Robert S. Murphy and Yasuhito Uezono},
  journal={Journal of Anesthesia},
  year={2014},
  volume={29},
  pages={475-479}
}
Tramadol has been used as an analgesic for several decades. µ-Opioid receptors (µORs) are the major receptors that mediate the analgesic effects of opioids. Although µORs have been thought to be one of the sites of action of tramadol, there has been no report that directly proves whether tramadol is an agonist of μOR or not. In this study, we examined the effects of tramadol and its main active metabolite O-desmethyltramadol (M1), on the function of µORs using Xenopus oocytes expressing cloned… 
What is the main mechanism of tramadol?
TLDR
The effects of tramadol on GPCRs, monoamine transporters, and ion channels are presented with a discussion of recent research on the mechanisms of tramADol.
Preclinical assessment of tramadol abuse potential: Effects of acute and repeated tramadol on intracranial self-stimulation in rats
TLDR
Tramadol has lower abuse potential than other abused MOR agonists and that repeated tramadol exposure produces relatively little enhancement of abuse potential of other MOR agonist candidates.
Tramadol induces changes in Δ-FosB, µ-opioid receptor, and p-CREB level in the nucleus accumbens and prefrontal cortex of male Wistar rat
TLDR
It is concluded that both CREB and ΔFosB played a role in tramadol dependence and increased MOR levels during tramadols treatments might be due to receptor desensitization.
Tramadol Treatment Induces Change in Phospho-Cyclic Adenosine Monophosphate Response Element-Binding Protein and Delta and Mu Opioid Receptors within Hippocampus and Amygdala Areas of Rat Brain
TLDR
HPC and AL are essential in the control of tramadol abuse and results showed that the level of p-CREB dose-dependently increased by acute and chronic tramadol exposure.
Inhibition by O-desmethyltramadol of glutamatergic excitatory transmission in adult rat spinal substantia gelatinosa neurons
TLDR
Results indicate that M1 inhibits the quantal release of L-glutamate from nerve terminals by activating μ-opioid but not noradrenaline and serotonin receptors; this inhibition is comparable in extent between monosynaptic primary-afferent Aδ-fiber and C- fiber transmissions.
ADME and toxicity considerations for tramadol: from basic research to clinical implications
TLDR
This review provides a comprehensive view on the pharmacokinetic, pharmacodynamic, and toxicity of tramadol with a deep look on its side effects, biochemical and pathological changes, and possible drug interactions.
Acute Tramadol-Induced Cellular Tolerance and Dependence of Ventral Tegmental Area Dopaminergic Neurons: An In Vivo Electrophysiological Study
TLDR
The tolerance and dependence effects of tramadol are related to the changes in the neuronal firing rate at the putative VTA-DA neurons.
Investigation on μ-opioid receptor in Sera of Iraqi Male addiction Tramadol or Methamphetamine
TLDR
The biochemical factor MOR can be used as a good marker to identify and follow up the addicted person and showed a highly significant decrease in the level of MOR of the two addicted groups in comparison with the healthy group.
A comparative study about the immunomodulatory effects of tramadol and metamizole in a murine model of postoperative ileus
TLDR
Tramadol is suggested as analgesia in immunological studies on POI in mice as it does not affect the underlying inflammation of POI.
Endogenous Opiates and Behavior: 2015
...
...

References

SHOWING 1-10 OF 24 REFERENCES
The Inhibitory Effects of Tramadol on Muscarinic Receptor-Induced Responses in Xenopus Oocytes Expressing Cloned M3 Receptors
TLDR
It is suggested that tramadol at clinically relevant concentrations inhibits M3 function via quinuclidinyl benzilate-binding sites, which may explain the modulation of neuronal function and the anticholinergic effects of tramadols.
The Inhibitory Effects of Tramadol on 5-Hydroxytryptamine Type 2C Receptors Expressed in Xenopus Oocytes
TLDR
The results suggest that tramadol inhibits 5-HT2CR function, and the mechanism of this inhibitory effect seems to involve competitive displacement of the5-HT binding to the 5- HT2CR, rather than via activation of the PKC pathway.
Pharmacological aspects of the effects of tramadol on G-protein coupled receptors.
TLDR
The effects of tramadol on monoamine transporters, GPCRs, and ion channels are presented, and recent research on the pharmacology of tramadol is discussed.
Influence of tramadol on neurotransmitter systems of the rat brain.
TLDR
The results indicate that tramadol enhances DA turnover via an opioid mechanism and closely resembles that of NA and 5-HT uptake inhibitors.
Analysis of the effects of anesthetics and ethanol on mu-opioid receptor.
TLDR
It is proposed that the electrophysiological assay in Xenopus oocytes expressing muOR-G(qi5) would be useful for analyzing the effects of anesthetics and analgesics on opioid receptor function.
Affinity, potency and efficacy of tramadol and its metabolites at the cloned human µ-opioid receptor
TLDR
Characterisation of the centrally active analgesic drug tramadol hydrochloride and its metabolites and an agonistic activity for the metabolites indicate that the metabolite (+)-M1 is responsible for the µ-opioid-derived analgesic effect.
Interaction of the central analgesic, tramadol, with the uptake and release of 5‐hydroxytryptamine in the rat brain in vitro
TLDR
An intact uptake system is necessary for the enhancement of extraneuronal 5‐HT concentrations by tramadol indicating an intraneuronal site of action.
Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids.
The influence of replacing the phenolic hydroxyl by the methoxy group on opioid receptor binding, analgesic and antitussive action was investigated in the corresponding couples morphine-codeine,
Sevoflurane Inhibits the µ-Opioid Receptor Function Expressed in Xenopus Oocytes
TLDR
It is suggested that sevoflurane would inhibit µOR function, and the mechanism of inhibition would be mediated by PKC, which is commonly used together with opioids in clinical practice.
Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro
TLDR
The results show that tramadol blocks noradrenaline uptake with selectivity as compared to dopamine uptake, and the interaction with the nor adrenaline transporter is stereoselective.
...
...