Altered functioning of monoamine-containing pathways descending from supraspinal structures to the spinal dorsal horn contributes to injury-induced sensitization of nociceptive transmission. Antidepressant drugs as typified by the dual serotonin (5-HT) and noradrenaline reuptake inhibitor duloxetine attenuate various signs and symptoms of persistent pain in animals and humans. The current study assessed whether dopamine receptor agonists could further enhance the antinociceptive activity of duloxetine in an animal model of injury-induced central sensitization, the rat formalin test. Duloxetine (3-100 mg/kg, s.c.), the dopamine D(1) receptor agonist SKF-82958 (0.1-1 mg/kg, s.c.) and the dopamine D(2) receptor agonist quinpirole (0.003-0.1 mg/kg, s.c.) all significantly attenuated spontaneous nociceptive behaviours during the second phase of the test; duloxetine and quinpirole also attenuated nociceptive behaviours during first phase and interphase. These antinociceptive actions of SKF-82958 and quinpirole were selectively antagonized by SCH 23390 and eticlopride respectively. Remarkably, when completely inactive doses of duloxetine (3 mg/kg) and SKF-82958 (0.3 mg/kg) were combined, a marked attenuation of second phase nociceptive behaviours occurred (P<0.05 vs vehicle), indicative of analgesic synergy. Similarly, when an active antinociceptive dose of quinpirole (0.03 mg/kg, P<0.05 vs vehicle) was combined with an inactive dose of duloxetine (3 mg/kg), a potentiation of duloxetine-mediated antinociception was observed (P<0.001 vs vehicle). Taken together, these results suggest that antidepressant drugs that can enhance the activity of 5-HT, noradrenaline and dopamine neurotransmission within nociceptive pathways should provide a broader spectrum of antinociception than dual mechanism of action reuptake inhibitors in animal models of injury-induced persistent nociception.