The role of the sigma receptor in prolonged pain was examined by assessing the effects of 1,3,di-o-tolylguanidine (DTG), a selective sigma receptor ligand, on the formalin test in mice. Formalin injected subcutaneously into the hindpaw produces a biphasic pain response: an acute phase of short duration followed by a longer-lasting tonic phase. DTG (10 mg/kg, i.p.) potently reduced pain behavior in the acute phase but increased pain behavior in the tonic phase. Rimcazole (5 and 10 mg/kg, i.p.), a selective sigma receptor antagonist, blocked both the DTG-induced decrease and increase in pain behavior observed in the acute and tonic phases, respectively. These data support previous findings indicating a modulatory role for the sigma receptor in nociceptive processes, and suggest that this receptor differentially modulates acute vs. tonic pain.