Milnacipran inhibits glutamatergic N-Methyl-D-Aspartate receptor activity in Spinal Dorsal Horn Neurons

Intrathecal injection of milnacipran (0.1？μmol), but not citalopram (0.1？μmol) and desipramine (0.1？μmol), followed by intrathecal injection of NMDA (1？μg) suppressed thermal hyperalgesia. Milnacipran (100 μM) reduced the amplitude of NMDA (56？±？3？%, 64？±？5？% of control)-, but not AMPA (98？±？5？%, 97？±？5？% of control)-mediated currents induced by exogenous application and dorsal root stimulation, respectively. Citalopram (100 μM) and desipramine (30 μM) had no effect on the amplitude of exogenous NMDA-induced currents. The number of pERK-positive neurons in the group treated with milnacipran (100 μM), but not citalopram (100 μM) or desipramine (30 μM), followed by NMDA (100 μM) was significantly lower compared with the NMDA-alone group.The antinociceptive effect of milnacipran may be dependent on the drug’s direct modulation of NMDA receptors in the superficial dorsal horn. Furthermore, in addition to inhibiting the reuptake of monoamines, glutamate NMDA receptors are also important for analgesia induced by milnacipran.