Pharmacology letter Accelerated communicationTramadol induces antidepressant-type effects in mice
Abstract
Tramadol is a clinically-effective, centrally-acting analgesic. This drug is a racemic mixture of two enantiomers, each one displaying different mechanisms: (+)tramadol displays opioid agonist properties and inhibits serotonin reuptake while (−)tramadol inhibit preferentially noradrenaline reuptake. The action of tramadol on the monoaminergic reuptake is similar to that of antidepressant drugs. Therefore, we have examined the effects of (±)tramadol, (+)tramadol and (−)tramadol in a test predictive of antidepressant activity, the forced swimming test in mice. Both (±)tramadol and its (−) enantiomer displayed a dose-dependent reduction on immobility; while the effect induced by the (+)enantiomer was not significant. Inhibition of noradrenaline synthesis, but not of serotonin synthesis, was capable of blocking the effect of (±)tramadol. The alpha-adrenoceptor antagonist phentolamine, as well as the alpha2-adrenergic antagonist yohimbine, and the beta-adrenoceptor blocker propranolol, countered the immobility-reducing action of (±)tramadol. Moreover, neither the serotoninergic blocker methysergide nor the opioid antagonist naloxone antagonized the effect of (±)tramadol. Our results show that (±)tramadol and (−)tramadol have antidepressant-like effect in mice, probably mediated by the noradrenergic system rather than the serotoninergic or opioidergic ones.
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Cited by (91)
The plausible mechanisms of tramadol for treatment of COVID-19
2021, Medical HypothesesCitation Excerpt :It can bind to μ-opioid receptors and inhibit norepinephrine and serotonin reuptake [20]. Through its capability to inhibit norepinephrine and serotonin reuptake, tramadol may possess antidepressant activity [18,39,40]. In this context, the antidepressant activities of tramadol may favor its indication for COVID-19 patients.
Currently, no single medication has been approved for the management of coronavirus disease-2019 (COVID-19) caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, drug repositioning by investigating the use of existing drugs for management of COVID-19 patients is considered a desperate need. Tramadol is a commonly prescribed analgesic drug for treatment of moderate to severe pain with less potential for dependence and respiratory depression. Multiple evidence support that tramadol is a promising drug for treatment of COVID-19 patients. Herein, we discuss the possible beneficial effects of using tramadol against SARS-CoV-2 infection and their underlying mechanism of action. The anti-inflammatory effect of tramadol may help to suppress the COVID-19 related cytokine storm through decreasing interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). Besides, tramadol activates natural killer (NK) and T-cells and enhances IL-2 secretion, which produce immune-enhancing effect against SARS-CoV-2. Recent studies confirmed that COVID-19 patients with acute respiratory failure showed increased fibrin formation and polymerization that may lead to thrombosis. Tramadol owing to its hypocoagulable effect may protect against venous thromboembolism in these patients. Moreover, tramadol can exert a cardioprotective effect via decreasing lactate dehydrogenase (LDH) level which is elevated in most of patients with COVID-19. Furthermore, the severity and mortality of COVID-19 have been correlated with old age patients, which may be due to the lack of antioxidant mechanisms and increased oxidative damage. Tramadol could protect COVID-19 patient from disease complications by increases the antioxidant enzymes superoxide dismutase and glutathione peroxidase while diminished malondialdehyde. More interestingly, tramadol as an effective analgesic and antitussive may have a beneficial effect on COVID-19 patients suffering from cough, headache, ache, and pain. The tramadol anti-psychotic effect may also protect against psychiatric disorders associated with SARS-CoV-2 infection. Moreover, tramadol has bactericidal activity against a wide range of pathogens including Pseudomonas aeruginosa which is common in severe COVID-19 patients leading to pneumonia with worse clinical outcomes. Therefore, we hypothesize that tramadol might be a promising adjuvant therapeutic option against SARS-CoV-2 infection. Based on that, tramadol should be considered as adjuvant therapy for COVID-19 clinical trials.
Involvement of NMDA receptors in the antidepressant-like effect of tramadol in the mouse forced swimming test
2017, Brain Research BulletinTramadol is an analgesic agent that is mainly used to treat moderate to severe pain. There is evidence that tramadol may have antidepressant property. However, the mechanisms underlying the antidepressant effects of tramadol have not been elucidated yet. Considering that fact that N-methyl-d-aspartate (NMDA) receptor signaling may play an important role in the pathophysiology of depression, the aim of the present study was to investigate the role of NMDA receptor signaling in the possible antidepressant-like effects of tramadol in the mouse forced swimming test (mFST). We found that tramadol exerted antidepressant-like effects at high dose (40 mg/kg, intraperitoneally [i.p.]) in the mFST. Co-administration of non-effective doses of NMDA receptor antagonists (ketamine [1 mg/kg, i.p.], MK-801 [0.05 mg/kg, i.p.], or magnesium sulfate [10 mg/kg, i.p.]) with sub-effective dose of tramadol (20 mg/kg, i.p.) exerted significant antidepressant-like effects in the mFST. The antidepressant-like effects of tramadol (40 mg/kg) was also inhibited by pre-treatment with non-effective dose of the NMDA receptor agonist NMDA (75 mg/kg, i.p.). Our data suggest a role for NMDA receptor signaling in the antidepressant-like effects of tramadol in the mFST.
Panicolytic-like effect of tramadol is mediated by opioid receptors in the dorsal periaqueductal grey
2017, Behavioural Brain ResearchTramadol is a synthetic opioid prescribed for the treatment of moderate to severe pain, acting as agonist of μ-opioid receptors and serotonin (5-HT) and noradrenaline (NE) reuptake inhibitor. This study evaluated the effects of tramadol in rats submitted to the elevated T-maze (ETM), an animal model that evaluates behavioural parameters such as anxiety and panic. Male Wistar rats were intraperitoneally (i.p.) treated acutely with tramadol (16 and 32 mg/kg) and were submitted to the ETM. Tramadol (32 mg/kg) promoted a panicolytic-like effect. Considering that dorsal periaqueductal grey (dPAG) is the main brain structure related to the pathophysiology of panic disorder (PD), this study also evaluated the participation of 5-HT and opioid receptors located in the dPAG in the panicolytic-like effect of tramadol. Seven days after stereotaxic surgery for implantation of a cannula in the dPAG, the animals were submitted to the test. To assess the involvement of 5-HT1A receptors on the effect of tramadol, we combined the 5-HT1A receptor antagonist, WAY100635 (0.37 nmol), microinjected intra-dPAG, 10 min prior to the administration of tramadol (32 mg/kg, i.p.). WAY100635 did not block the panicolytic-like effect of tramadol. We also associated the non-selective opioid receptor antagonist, naloxone, systemically (1 mg/kg, i.p.) or intra-dPAG (0.5 nmol) administered 10 min prior to tramadol (32 mg/kg, i.p.). Naloxone blocked the panicolytic-like effect of tramadol in both routes of administrations, showing that tramadol modulates acute panic defensive behaviours through its interaction with opioid receptors located in the dPAG.
Tramadol: Effects on sexual behavior in male rats are mainly caused by its 5-HT reuptake blocking effects
2017, NeuropharmacologyTramadol is a well-known and effective analgesic. Recently it was shown that tramadol is also effective in human premature ejaculation. The inhibitory effect of tramadol on the ejaculation latency is probably due to its mechanism of action as a μ-opioid receptor agonist and noradrenaline/serotonin (5-HT) reuptake inhibitor. In order to test this speculation, we tested several doses of tramadol in a rat model of male sexual behavior and investigated two types of drugs interfering with the μ-opioid and the 5-HT system. First the μ-opioid receptor agonist properties of tramadol were tested with naloxone, a μ-opioid receptor antagonist. Second, the effects of WAY100,635, a 5-HT1A receptor antagonist, were tested on the behavioral effects of tramadol. Finally the effects of paroxetine, a selective serotonin reuptake inhibitor, combined with naloxone or WAY100,635 treatment, were compared to the effects of tramadol combined with these drugs.
Results showed that naloxone, at a sexually inactive dose, could only partially antagonize the inhibitory effect of tramadol. Moreover, low and behaviorally inactive doses of WAY100,635, strongly decreased sexual behavior when combined with a behaviorally inactive dose of tramadol. Finally we showed that the effects of paroxetine on sexual behavior resembled the effects of tramadol, indicating that tramadol's inhibitory effects on sexual behavior are primarily and mainly caused by its SSRI properties and that its μ-opioid receptor agonistic activity only contributes marginally. These findings support the hypothesis that tramadol exerts inhibition of premature ejaculations in men by its 5-HT reuptake inhibiting properties.
Cortical excitability in tramadol dependent patients: A transcranial magnetic stimulation study
2016, Drug and Alcohol DependenceAddiction to tramadol, a widely used analgesic, is becoming increasingly common. Tramadol can also induce seizures even after a single clinical dose. We tested whether the epileptogenicity of tramadol was associated with any changes in cortical excitability and inhibitory transmission using transcranial magnetic stimulation (TMS).
The study included 16 tramadol dependent patients and 15 age and sex matched healthy volunteers. Clinical evaluation was conducted using an addiction severity index. TMS assessment of excitability was conducted on the motor cortex since the response to each TMS pulse at that site is easily measured in terms of the amplitude of the twitches it evokes in contralateral muscles. Measures included resting and active motor threshold (RMT and AMT respectively), motor evoked potential (MEP) amplitude, cortical silent period (CSP) duration, transcallosal inhibition (TCI), and short interval intracortical inhibition and facilitation (SICI and ICF respectively). Urinary level of tramadol was measured immediately before assessing cortical excitability in each patient.
RMT and AMT were significantly lower, the duration of the CSP was shorter and SICI was reduced in patients compared with the control group. These findings are suggestive of increased neural excitability and reduced GABAergic inhibition following exposure to tramadol. Also there were negative correlations between the severity of tramadol dependence and a number of cortical excitability parameters (AMT, RMT, and CSP with P = 0.002, 0.005, and 0.04 respectively).
The results provide evidence for hyperexcitability of the motor cortex coupled with inhibitory deficits in tramadol dependent patients.
Efficacy of tramadol–acetaminophen tablets in low back pain patients with depression
2015, Journal of Orthopaedic ScienceTramadol–acetaminophen tablets are currentlyused to treat pain, including that of degenerative lumbar disease. Although there are many reports on tramadol–acetaminophen tablets, treatment outcomes in low back pain (LBP) patients with depression remain uncertain.This study investigated the outcomes of LBP patients with depression treated with tramadol–acetaminophen tablets.
Of 95 patients with chronic LBP, 70 (26 men,44 women; mean age 64 years) who were judged as having depression by the Self-Rating Depression Scale (SDS) wereincluded in this study. In this trial, patients received one of two randomly assigned 8-week treatment regimes: tramadol–acetaminophen (Tramadol group, n = 35) and non-steroidal anti-inflammatory drugs (NSAIDs) (NSAID group, n = 35). In addition to completing self-report questionnaires, patients provided demographic and clinical information. All patients were assessed using a Numerical Rating Scale (NRS), Oswestry Disability Index (ODI), Pain DisabilityAssessment Scale (PDAS), Hospital Anxiety and Depression Scale (HADS), SDS, and Pain Catastrophizing Scale (PCS).
After 8 weeks’ treatment, the NRS and SDS scoreswere lower in the Tramadol group than in the NSAID group (p < 0.05). There were no significant differences in the ODI,PDAS, and PCS scores between the groups (p = 0.47, 0.09, 0.47). Although there was no difference in the anxiety componentof the HADS between the groups (p = 0.36), the depression component was lower in the Tramadol group than in the NSAID group (p < 0.05). There was no significant difference between groups in the percentage of patients with treatment-associated adverse events.
This investigation found that tramadol–acetaminophen is effective for reducing LBP and provided a prophylactic antidepressant effect in chronic LBP patients with depression.
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Becaria F.P.I Univeristy of Cádiz.