Milnacipran inhibits glutamatergic N-methyl-D-aspartate receptor activity in spinal dorsal horn neurons.
BACKGROUND
Antidepressants, which are widely used for treatment of chronic pain, are thought to have antinociceptive effects by blockade of serotonin and noradrenaline reuptake. However, these drugs also interact with various receptors such as excitatory glutamatergic receptors. Thermal hyperalgesia was induced by intrathecal injection of NMDA in rats. Paw withdrawal latency was measured after intrathecal injection of antidepressants. The effects of antidepressants on the NMDA and AMPA-induced responses were examined in lamina II neurons of rat spinal cord slices using the whole-cell patch-clamp technique. The effects of milnacipran followed by application of NMDA on pERK activation were also investigated in the spinal cord.


RESULTS
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.


CONCLUSIONS
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.
Department of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachi, Japan. kohno-t@umin.net
Tatsuro
T
Kohno
Masafumi
M
Kimura
Mika
M
Sasaki
Hideaki
H
Obata
Fumimasa
F
Amaya
Shigeru
S
Saito
D000775:Anesthesia, Spinal; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D015283:Citalopram / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D000078764:Milnacipran; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D000928:Antidepressive Agents; D003521:Cyclopropanes; D016194:Receptors, N-Methyl-D-Aspartate; D015283:Citalopram; D000078764:Milnacipran; D003891:Desipramine