Tricyclic antidepressant's effects on visceral nociception and its underlying mechanisms

Objectives: Tricyclic antidepressants (TCAs) like Amitriptyline are established drugs in the treatment of IBS. Lately modern 5-HT agonists have demonstrated the importance of serotonergic mechanisms on visceral perception. The heterogeneity of potential drug actions of TCA's obviously plays a crucial role in their efficacy on visceral pain. In contrary, SSRIs fail to show these effects.

Aims: This study aims to characterize the influence of amitriptyline on visceral nociception. Reserpine was used to antagonize TCA's sertonergic actions in order to discriminate these effects from others.

Methods: We performed colorectal distensions (CRD) with a barostat device in male Lewis rats and assessed the visceromotor response (VMR) to tonic distension by abdominal wall electromyography. 2 hours prior to CRD we either applied Amitriptyline (15mg/kg) or Reserpine (1.5mg/kg) singularly or in coadministration intraperitoneally (i.p.). Controls received saline i.p.. Serotonin (5-HT) serum levels were determined by HPLC protocol.

Results: Administration of Amitriptyline caused a significant decrease in VMR compared to controls [area under the curve (AUC) to CRD in controls was 5841µV(±2438µV), in 15mg/kg: 3766µV(±1626µV;p<0.05)]. In rats pretreated with Reserpine the AUC under CRD was 7359µV(±1418µV;p<0.001). Coadministration of both drugs resulted in an AUC of 6329µV(±1158µV). 5-HT levels were increased in amitriptyline pretreated rats compared to controls. Significantly lower 5-HT levels were found in rats pretreated with reserpine as well as in the combination of reserpine+TCA.

Conclusions: Amitriptyline has a significant antinociceptive effect, elevating the 5-HT serum levels. Administration of Reserpine in contrary resulted in a significant increase of the VMR, correlating with low 5-HT serum levels. Coadministration of both drugs attenuated Reserpine's effects on VMR, without any effect on the low 5-HT levels. This could be explained by TCA's additional effects on visceral nociception. Serotonergic effects seem to play an important role in TCA's mode of action on attenuation of visceral nociception but anticholinergic effects or presumably direct antinociceptive effects of these drugs should not be underestimated and are subject of further investigations.