Antidepressant-like Effect Of Tramadol Research Articles

Involvement of NMDA receptors in the antidepressant-like effect of tramadol in the mouse forced swimming test.

Tramadol 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 (40mg/kg, intraperitoneally [i.p.]) in the mFST. Co-administration of non-effective doses of NMDA receptor antagonists (ketamine [1mg/kg, i.p.], MK-801 [0.05mg/kg, i.p.], or magnesium sulfate [10mg/kg, i.p.]) with sub-effective dose of tramadol (20mg/kg, i.p.) exerted significant antidepressant-like effects in the mFST. The antidepressant-like effects of tramadol (40mg/kg) was also inhibited by pre-treatment with non-effective dose of the NMDA receptor agonist NMDA (75mg/kg, i.p.). Our data suggest a role for NMDA receptor signaling in the antidepressant-like effects of tramadol in the mFST.

Comparative efficacy of behavioral despair models in depicting antidepressant-like effect of tramadol

Background: Experimental evaluation of antidepressants (ADs) in diverse animal models is the need of time. There is a constant search for newer models with ease and rapid screening of AD activity. As earlier studies highlight AD effect of tramadol in animal models, the study was undertaken to compare antidepressant-like effect of tramadol in two models of behavioural despair in mice. Methods: Tramadol was administered intraperitoneally (i.p.) at two different doses of 20 and 40 mg/kg, once daily for 7 days to Swiss albino mice. The immobility period of control and drug-treated mice was recorded in tail suspension test (TST) and forced swim test (FST). The antidepressant (AD) effect of tramadol was compared with control (NS) and reference drug imipramine (10 mg/kg, p.o.), administered orally (p.o.) for seven successive days. Results: Tramadol in tail suspension test (TST) produced significant antidepressant effect at 20 and 40 mg/kg doses, as depicted by reduction in immobility period of drug-treated mice compared to control group. The efficacy of tramadol at dose of 40 mg/kg was comparable to that of imipramine treated group (p 0.05). Conclusion : The results of the present study depict antidepressant-like activity of tramadol in both the models of depression TST and FST. But TST in mice seems to be more efficacious in appraising the antidepressant like effect of tramadol.

Evidence for the involvement of the noradrenergic system, dopaminergic and imidazoline receptors in the antidepressant-like effect of tramadol in mice

The involvement of the noradrenergic system, imidazoline, dopaminergic and adenosinergic receptors in the antidepressant-like action of tramadol in the mouse forced swimming test (FST) was evaluated in this study. The antidepressant-like effect of tramadol (40 mg/kg, per oral, p.o.) in the FST was blocked with yohimbine (1 mg/kg, i.p., an α 2-adrenoceptor antagonist), α-methyl-para-tyrosine methyl ester (AMPT, 100 mg/kg, i.p., an inhibitor of tyrosine hydroxylase), efaroxan (1 mg/kg, i.p., an imidazoline I 1/α 2-adrenoceptor antagonist), idazoxan (0.06 mg/kg, i.p., an imidazoline I 2/α 2-adrenoceptor antagonist), antazoline (5 mg/kg, i.p., a ligand with high affinity for the I 2 receptor), haloperidol (0.2 mg/kg, i.p., a non selective dopamine receptor antagonist), SCH23390 (0.05 mg/kg, subcutaneously, s.c., a dopamine D 1 receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D 2 and D 3 receptor antagonist) but was not reversed by prazosin (1 mg/kg, intraperitoneally, i.p., an α 1-adrenoceptor antagonist) and caffeine (3 mg/kg, i.p., a nonselective adenosine receptor antagonist). Monoamine oxidase-A and -B (MAO-A and MAO-B) activities were neither inhibited in the whole brain nor in specific brain regions of mice treated with tramadol. These data demonstrated that the antidepressant-like effect caused by oral administration of tramadol in the mouse FST is mediated by the noradrenergic system, dopaminergic and imidazoline receptors.

Involvement of different types of potassium channels in the antidepressant-like effect of tramadol in the mouse forced swimming test

Administration of tramadol elicited an antidepressant-like effect in the rat forced swimming test (FST) by a mechanism dependent on the inhibition of the L-arginine-nitric oxide (NO)-guanylate cyclase pathway. Since it has been reported that NO can activate different types of potassium (K +) channels in several tissues, the present study investigated the possibility of synergistic interactions between different types of K + channel inhibitors and tramadol in the mouse FST. Intracerebroventricular pretreatment of mice with tetraethylammonium (TEA, a non-specific inhibitor of K + channels, 25 pg/site), glibenclamide (an ATP-sensitive K + channel inhibitor, 0.5 pg/site) or charybdotoxin (a large- and intermediate conductance calcium-activated K + channel inhibitor, 25 pg/site) was able to produce a synergistic action of a subeffective dose of tramadol (1 mg/kg, p.o.). Conversely, pretreatment with apamin (a small-conductance calcium-activated K + channel inhibitor, 10 pg/site) did not modify the action of a subeffective dose of tramadol (1 mg/kg, p.o.). Administration of tramadol and the K + channel inhibitors, alone or in combination, did not affect the number of crossings and rearings in the open field test (OFT). Reduction in the immobility time elicited by an active dose of tramadol (40 mg/kg, p.o.) in the FST was prevented by pretreatment of mice with cromakalim (a K + channel opener, 10 µg/site, i.c.v.), without affecting the number of crossings and rearings in the OFT. Thus, our findings clearly suggest that oral acute administration of tramadol produces antidepressant-like effect on the FST in mice by a mechanism that involves the K + channels.

Involvement of l-arginine–nitric oxide–cyclic guanosine monophosphate pathway in the antidepressant-like effect of tramadol in the rat forced swimming test

Tramadol is a centrally acting analgesic which is used mainly for the treatment of moderate or severe pain. It is a synthetic opioid in the aminocyclohexanol group that binds weakly to μ-opioid receptors. Since it has been suggested that both opioid and monoaminergic systems play a role in depressive disorders, tramadol has been studied in the forced swimming test (FST). The present study was designed to explore the antidepressant activity of tramadol in rat FST and its possible mechanisms of action. The involvement of l-arginine–nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of tramadol was investigated. Treatment with tramadol, given (30 min earlier) by oral route (p.o.) at the doses of 10, 20 and 40 mg/kg, decreased immobility time in the FST. Pretreatment of rats with l-arginine (250 mg/kg, intraperitoneal, i.p., a nitric oxide precursor) or sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor, PDE5) significantly reversed the reduction in immobility time elicited by tramadol (20 mg/kg, p.o.) in the FST. Treatment of animals with a sub-effective dose of tramadol (5 mg/kg, p.o.) produced a synergistic antidepressant-like effect with N G-nitro- l-arginine (L-NNA, 3 mg/kg, i.p., an inhibitor of nitric oxide synthase) or with 7-nitroindazole (7-NI, 9 mg/kg i.p., a specific neuronal nitric oxide synthase inhibitor) in the FST. Pretreatment of animals with methylene blue (3.75 mg/kg i.p., an inhibitor of NO synthase and soluble guanylate cyclase — sGC) or (1 H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one) (ODQ, 2 mg/kg, i.p., a specific inhibitor of sGC) significantly caused a synergistic effect with a sub-effective dose of tramadol (5 mg/kg, p.o.) in the FST. In the present study, different doses of tramadol and the combination with the l-arginine–NO–cGMP pathway modulators had no effect on the locomotor activity of rats in the open-field test. Thus, our findings suggest that the acute administration of tramadol produces antidepressant-like effect in the rat FST by a mechanism that involves the inhibition of l-arginine–NO–cGMP pathway.

Evaluation of antidepressant activity of tramadol in mice

Objective:To evaluate antidepressant like effect of tramadol in mice.Materials and Methods:Tramadol was administered at three different doses (10,20 and 40 mg/kg, i.p) once daily for 7 days to Swiss albino mice of either sex. The immobility period of control and drug treated mice were recorded in tail suspension test (TST).The antidepressant effect of tramadol was compared to that of fluoxetine (20 mg/kg, i.p), administered for seven days.Results:Tramadol produced significant antidepressant effect at all the doses, as indicated by reduction in immobility times as compared to control. The efficacy of tramadol at doses of 20 and 40 mg/kg was comparable with that of fluoxetine. Tramadol at 10 mg/kg dose showed significantly less antidepressant activity compared to fluoxetine. Conclusion:The results of the present study indicate antidepressant like activity of tramadol.

Antidepressant-like effect of tramadol in the unpredictable chronic mild stress procedure: possible involvement of the noradrenergic system

Tramadol, which inhibits the reuptake of noradrenaline and serotonin, is effective in animal models of depression. Its antidepressant-like effects may be mediated mainly by the noradrenergic system. This study investigated the role of the noradrenergic system in the antidepressant-like effects of tramadol and desipramine in the unpredictable chronic mild stress model. We assessed the involvement of beta-adrenoreceptors, particularly beta2-receptors in the activity of these drugs. In addition, we measured the level of noradrenaline and its metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the locus coeruleus, hypothalamus, hippocampus and cerebellum in stressed mice. Unpredictable chronic mild stress induced a degradation of coat state and decreased grooming behaviour in the splash test, which was reversed by the chronic administration of tramadol (20 mg/kg) and desipramine (10 mg/kg). The nonselective beta-adrenoreceptor antagonist propranolol (5 mg/kg, intraperitoneally) and the selective beta2-receptor antagonist ICI 118,551 (2 mg/kg, intraperitoneally) reversed the antidepressant-like effects of tramadol and desipramine. Moreover, chronic tramadol and desipramine treatment increased the level of noradrenaline (NA) and MHPG in the locus coeruleus but not in the cerebellum, whereas only MHPG level was increased in the hypothalamus. Tramadol, however, increased the levels of MHPG and NA in the hippocampus, whereas desipramine only increased NA level. These data support the view that the noradrenergic system plays an important role in the antidepressant-like action of tramadol.

Differential role of 5-HT1A and 5-HT1B receptors on the antinociceptive and antidepressant effect of tramadol in mice

Tramadol, (1RS,2RS)-2-[(dimethylamine)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is an atypical analgesic which binds weakly to ì-opioid receptors and enhances the extra-neuronal concentration of noradrenaline and serotonin by interference with both the uptake and release mechanisms. The present study was undertaken to evaluate the potential role of 5-HT1A and 5-HT1B receptors on the analgesic and antidepressant-like effect of tramadol. The effect of either a selective 5-HT1A receptor antagonist (WAY 100635; N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide; 0.2-0.8, 8 mg/kg) or a selective 5-HT1B receptor antagonist (SB 216641; N-[3-(3-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide; 0.2-0.8, 8 mg/kg) was investigated in mice in combination with tramadol by means of the hot-plate test, a phasic nociceptive model, and the forced swimming test, a paradigm aimed at screening potential antidepressants. The results showed that WAY 100635 enhanced the antinociceptive effect and produced a large decrease in the antidepressant-like effect of tramadol. In contrast, SB 216641 did not significantly modify either the analgesic or the antidepressant-like effects of tramadol. These findings suggest that 5-HT1A receptors modulate the analgesic and the antidepressant-like effects of tramadol in differing ways. The results suggest the involvement of the 5-HT1A autoreceptors from the raphe nuclei and spinal 5-HT1A receptors in the antinociceptive effect. In contrast, the 5-HT1A receptors located in the forebrain may be responsible for the blockade of the antidepressant-like effect of tramadol. 5-HT1B receptors seem not to modify these effects in the models investigated.

Effects of desipramine and tramadol in a chronic mild stress model in mice are altered by yohimbine but not by pindolol

This study investigated the antidepressant-like effects of a chronic treatment with either tramadol (20 mg/kg, i.p.) or desipramine (10 mg/kg, i.p.) in the unpredictable chronic mild stress model of depression in BALB/c mice. Mice were first submitted to a 2 week drug-free unpredictable chronic mild stress before the onset of the treatments. The unpredictable chronic mild stress regimen induced a degradation of the state of the coat and decreased the grooming behaviour in the splash test. These physical and behavioural abnormalities were counteracted by tramadol and desipramine. Furthermore, we observed neither a significant acceleration nor diminution by pindolol (5-HT 1A/1B receptor antagonist, 10 mg/kg, i.p.) on the antidepressant-like actions of desipramine and tramadol whereas yohimbine (α 2-adrenergic receptor antagonist, 2 mg/kg, i.p.) antagonized the antidepressant-like effects of both drugs during the unpredictable chronic mild stress regimen. The results of the study support the suggestion that antidepressant-like effect of tramadol and desipramine in mice in the unpredictable chronic mild stress model is mediated by the noradrenergic system rather than the serotonergic system.