Milnacipran inhibits glutamatergic N-methyl-D-aspartate receptor activity in spinal dorsal horn neurons.

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Kohno T, Kimura M, Sasaki M, Obata H, Amaya F, Saito S

Milnacipran inhibits glutamatergic N-methyl-D-aspartate receptor activity in spinal dorsal horn neurons.

Mol Pain. 2012 Jun 19;8:45. doi: 10.1186/1744-8069-8-45.

PubMed ID

22716121 [ View in PubMed

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Abstract

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 mumol), but not citalopram (0.1 mumol) and desipramine (0.1 mumol), followed by intrathecal injection of NMDA (1 mug) suppressed thermal hyperalgesia. Milnacipran (100 muM) 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 muM) and desipramine (30 muM) had no effect on the amplitude of exogenous NMDA-induced currents. The number of pERK-positive neurons in the group treated with milnacipran (100 muM), but not citalopram (100 muM) or desipramine (30 muM), followed by NMDA (100 muM) 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Milnacipran	NMDA receptor (Protein Group)	Protein group	Humans	Unknown	Inhibitor	Details