Acetaminophen was administered to mice by spinal (intrathecal, i.t.) injection alone or with phentolamine (11.3 microg = 0.03 micromol). Acetaminophen produced dose-related antinociception in the abdominal irritant test with an ED(50) value of 137.2 microg (0.9 micromol) Phentolamine had no effect. For combined administration, the potency of acetaminophen was significantly increased (ED50=24.4 vs. 137.2 microg), indicative of multiplicative interaction and strong synergism. These results reveal the significant and surprising interaction of spinal cord adrenoceptors or ion channel subtypes with acetaminophen-induced antinociception.