Cooperative opioid and serotonergic mechanisms generate superior antidepressant-like effects in a mice model of depression

Although complete remission of symptoms is the goal of any depression treatment, many patients fail to attain or maintain a long-term, symptom-free status. The opioid system has been implicated in the aetiology of depression, and some preclinical and clinical data suggest that opioids possess a genuine antidepressant-like effect. This study aimed to investigate a potential antidepressant strategy combining different classes of monoaminergic compounds with the weak mu-opioid agonist codeine in the tail suspension test in mice, a paradigm aimed at screening potential antidepressants. The results showed that codeine produced an antidepressant-like effect when administered alone, that was effectively antagonized by the opioid antagonist naloxone. The combination of subeffective doses of codeine with the selective serotonin reuptake inhibitors (fluoxetine or citalopram) lead to an accentuated reduction in immobility time. In contrast, immobility time remained unchanged when codeine was combined with a noradrenaline reuptake inhibitor (desipramine) or with a noradrenaline/serotonin reuptake inhibitor (duloxetine). The immobility time also remained unchanged with the combination of subeffective doses of codeine plus (+/-)-tramadol (weak mu-opioid agonist with serotonin/noradrenaline reuptake inhibitor properties) or (-)-tramadol (noradrenaline reuptake inhibitor). Conversely, the combination with (+)-tramadol (mu-opioid agonist with serotonin reuptake inhibitor properties) produced a large decrease in the immobility time. All these combinations were without effects on motor behaviour in mice. These data support the hypothesis that a combination of classical serotonergic antidepressants and weak opioid receptor agonists may be a helpful new strategy in the treatment of refractory depression.