Animal models of chronic pain serve as an experimental basis for testing new therapeutic interventions and for mechanistic investigations. In an animal model of chronic pain, based on the injection of formalin into the paw of a rodent, inhibitors of noradrenaline reuptake such as nisoxetine, nortriptyline and maprotiline and dual inhibitors of the noradrenaline and serotonin reuptake such as imipramine and milnacipran produce potent anti-nociceptive effects, whereas selective serotonin reuptake inhibitors, such as fluvoxamine, are much less potent. In another model, neuropathic pain resulting from the chronic constriction injury of the sciatic nerve was prevented by the dual uptake inhibitor, venlafaxine. The experimental model involving ligation of the 5th spinal nerve induces behavioural signs in rats and mice that are similar to the symptoms of human neuropathic pain. In this model amitriptyline, a non-selective serotonin and noradrenaline reuptake blocker, the preferential noradrenaline reuptake inhibitor, desipramine and the selective serotonin and noradrenaline reuptake inhibitors, milnacipran and duloxetine, produce a decrease in pain sensitivity whereas the selective serotonin reuptake inhibitor, fluoxetine, is ineffective. Antidepressants acting on the noradrenergic or both the noradrenergic and serotonergic systems thus appear to be more effective than those working on the serotonin system alone.