The effect of agomelatine on intracellular calcium signaling in sensory neurons

The efficacy of agomelatine, a new antidepressant approved by the European Union Pharmaceutical Agency in 2009 under the trade name valdoxan, on pain has recently been demonstrated by studies done. However, it is not known which mechanism leads to the formation of analgesic activity. In this study, the mechanism of action of agomelatine in peripheral nociception was investigated. For this purpose, effects of agomelatine on intracellular calcium ([Ca+ 2]i) levels were looked in isolated rat dorsal root ganglion (DRG) neurons. Isolated DRG neurons were loaded with 1 μmol fura-2 AM and Ca+2 responses were assessed by using proportional measurement. Fura-2 AM loaded DRG cells were excited 340 nm and 380 nm, and emission was recorded at 510 nm by using digital microscopic calcium imaging system. Change in [Ca+2]i concentration determined with a change in fluorescence ratio of 340 nm / 380 nm in DRG neurons. Agomelatine caused to increase dose-dependent in [Ca+2]i . The mean 340 nm/380 nm rations were detected (baseline 100,0±0.0 % vs agomelatine): % 104,8±3,2 (1 μM agomelatine, n=43), % 117,6±2,4 (10 μM agomelatine, n=62) and % 164,2±2,8 (100 μM agomelatine, n=48). The G protein inhibitor pertussis toxin (PTX) suppresses the agomelatine-induced calcium responses (from 100,0±0.0 % to 7,9±3,6 %, n=61 cells). When agomelatin is administered after treatment with the phospholipase C (PLC) inhibitor U-73122 and after treatment with the protein kinase C (PKC) inhibitor chelerythrine chloride, the increase in agomelatine-induced calcium responses significantly decreases (from 100,0±0.0 % to 12,3±3,5 %, n=39 cells) (from 100,0±0.0 % to 28,6±4,2 %, n=27 cells). We first demonstrated that agomelatine mediate peripheral nociceptive signalling through the mechanism that involves G protein, PLC and PKC-dependent changes in intracellular calcium levels in rat primary sensory neurons. Agomelatine which a antidepressant that high-affinity melatonergic (MT1 and MT2) receptor agonist (MT1: pKi=9.92; MT2: pKi=9.24) and serotoninergic (5-HT2C) (pKi=6.2) receptor antagonist in low sensitivity, it is also thought to play a role in pain recognition process.