High comorbidity is described between depression and pain disorders. Monoaminergic reuptake inhibitors represent the first choice of treatment for depression and serotonin and norepinephrin reuptake inhibitors are also recommended for the treatment of neuropathic pain disorders. We aims at evaluating analgesic effects of these drugs in animal models sharing anxio-depressive and painful phenotype. We first developed tests to assess pain sensitivity in mice and analgesic properties of pharmacological compounds. Depressive phenotype was assessed using various behavioural paradigms of anxiety/depression.We thus show that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), provide antinociceptive effects in a mice model of anxiety-depression: the CORT model. Fluoxetine may thus exert its analgesic effect by modulating the affective aspect of pain in addition to a putative influence on sensory mechanisms. Moreover we characterized analgesic effects of a new generation of antidepressant, the triple reuptake inhibitors, which simultaneously potentialisate serotoninergic, noradrenergic and dopaminergic neurotransmission, in a mice model of oxaliplatin-induced neuropathy. Our results support that indatraline provide a better analgesic profile than escitalopram and venlafaxine in pain relief in oxaliplatin-treated mice. Although other investigations are required to quantify the putative involvement of DA in the therapeutic action of indatraline, the benefit can be attributed to this additional component. Indeed, reinforcement of descending control pathways though 5-HT and NE systems has been proposed to participate in the analgesic properties of dual reuptake inhibitors. The fact that indatraline was able to enhance dopaminergic transmission in the Anterior Cingulate Cortex argues in favor of a more potent action upon this inhibitory descending control of pain. Results with indatraline in the depression paradigm cannot rule out the possibility that the antidepressant property of the TRI accounts for its analgesic effect.This work provides a support for the need of animal models sharing anxio/depressive and painful phenotype in order to define mechanism responsible for such co-mobidity and optimize the development of newer antidepressants and pain killers.
