What is the main mechanism of tramadol?

@article{Minami2015WhatIT,
  title={What is the main mechanism of tramadol?},
  author={Kouichiro Minami and Junichi Ogata and Yasuhito Uezono},
  journal={Naunyn-Schmiedeberg's Archives of Pharmacology},
  year={2015},
  volume={388},
  pages={999-1007}
}
Tramadol is an analgesic that is used worldwide for pain, but its mechanisms of action have not been fully elucidated. The majority of studies to date have focused on activation of the μ-opioid receptor (μOR) and inhibition of monoamine reuptake as mechanisms of tramadol. Although it has been speculated that tramadol acts primarily through activation of the μOR, no evidence has revealed whether tramadol directly activates the μOR. During the past decade, major advances have been made in our… 
Synergism between gabapentin–tramadol in experimental diabetic neuropathic pain
TLDR
The findings of the present study suggest that the combination of gabapentin and tramadol could be a useful strategy for the treatment of pain induced by diabetic neuropathy.
EEG and Sleep Effects of Tramadol Suggest Potential Antidepressant Effects with Different Mechanisms of Action
TLDR
The sleep-related and qEEG effects of tramadol suggest antidepressant-like properties, including specific beneficial effects in selected patient groups, and raise the possibility of a faster acting antidepressant action.
Tramadol Abuse and Sexual Function.
Caffeine attenuates seizure and brain mitochondrial disruption induced by Tramadol: the role of adenosinergic pathway
TLDR
It is suggested that the adenosinergic system is involved in seizure induced by TR and meanwhile, inhibition of adenosine receptors can decrease the TR seizure threshold and also decrease the induced oxidative damage in the brain mitochondria.
Are Opioids Effective in Relieving Neuropathic Pain?
  • E. Schembri
  • Biology, Medicine
    SN Comprehensive Clinical Medicine
  • 2018
TLDR
The literature reviewed showed that the mechanisms underlying NP, may themselves contribute to the reduced effect of opioids in this condition, and there is still no robust evidence that any specific opioid agent is better than any other one for NP, but it is possible that opioids targeting multiple mechanisms may provide benefit.
Peripheral Tramadol in Dentistry: A New Use for an Old Drug
TLDR
Some of the current efforts develop to explore the peripheral Tramadol in dentistry are summarized; “a new use for an old drug”.
Tramadol with or without paracetamol (acetaminophen) for cancer pain.
TLDR
To assess the benefits and adverse effects of tramadol with or without paracetamol (acetaminophen) for cancer-related pain, the Cochrane Central Register of Controlled Trials and three clinical trials registry databases were searched.
...
...

References

SHOWING 1-10 OF 70 REFERENCES
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.
The Analgesic Drug, Tramadol, Acts as an Agonist of the Transient Receptor Potential Vanilloid-1
TLDR
The findings of this study strongly support the intriguing and novel concept that tramadol acts as an agonist of TRPV1.
µ-Opioid receptor activation by tramadol and O-desmethyltramadol (M1)
TLDR
The effects of tramadol and its main active metabolite O-desmethyltramadol (M1), on the function of µ ORs using Xenopus oocytes expressing cloned human µORs are examined.
The tramadol metabolite O-desmethyl tramadol inhibits substance P-receptor functions expressed in Xenopus oocytes.
TLDR
The results suggest that the tramadol metabolite ODT inhibits the SPR functions, which may be independent of activation of PKC-mediated pathways.
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 Effects of the Tramadol Metabolite O-Desmethyl Tramadol on Muscarinic Receptor-Induced Responses in Xenopus Oocytes Expressing Cloned M1 or M3 Receptors
TLDR
O-desmethyl tramadol inhibits functions of M1 receptors but has little effect on those of M3 receptors, which may help to explain its neural function.
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.
The Tramadol Metabolite, O-Desmethyl Tramadol, Inhibits 5-Hydroxytryptamine Type 2C Receptors Expressed in Xenopus Oocytes
TLDR
O-desmethyl tramadol inhibits 5-HT2CR, a G-protein-coupled receptor that is expressed widely within brain and that mediates several effects of5-HT, including nociception, feeding, and locomotion, which provides further insight into the pharmacological properties of tramadols.
The Effects of Tramadol and Its Metabolite on Glycine, γ-Aminobutyric AcidA, and N-Methyl-d-Aspartate Receptors Expressed in Xenopus Oocytes
TLDR
It is suggested that glycine receptors do not provide the antinociceptive effect of tramadol and that the inhibition of GABAA receptors at large concentration might correlate with convulsions.
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.
...
...