Herein, we evaluated the involvement of the cannabinoid system in serotonin-mediated peripheral antinociception. After administration of intraplantar prostaglandin E₂ (PGE₂), animals demonstrating increased pain sensitivity were subjected to a paw pressure test. Serotonin induced a peripheral antinociceptive effect (250 ng); this effect was reversed by the α₁-adrenoceptor antagonist prazosin, α₂-adrenoceptor antagonist yohimbine, and the β-adrenoceptor antagonist propranolol. Reboxetin amplified the antinociceptive effects of low-dose serotonin. Our data suggest the existence of interactions between the serotonergic and noradrenergic systems during peripheral antinociception.