Tramadol 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 alpha 2-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.