Limitations of two TCA's serotonergic effects on visceral nociception in a rat model

Aims: Tricyclic antidepressants (TCA) like amitriptyline (AM) or desipramine (DE) are established drugs in the treatment of abdominal pain in IBS patients. Their serotonergic properties are assumed to be responsible for this effect. Clinical data suggests that SSRIs have lower potential in treating those symptoms. Thus, we postulate that the heterogeneity of TCA's effects plays a crucial role in their efficacy on visceral pain.

Aims: We aim to characterize the influence of two TCAs on visceral nociception. Reserpine (RS) 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 EMG. 2 hours prior to CRD we either applied AM (15mg/kg), DE (15mg/kg) or RS (1.5mg/kg) singularly or in coadministration (AM+RS or DE+RS) intraperitoneally (i.p.). Controls received saline i.p.. Serotonin (5-HT) serum levels were determined by HPLC protocol.

Results: Administration of TCAs caused a significant decrease in VMR compared to controls [area under the curve (AUC) to CRD in controls was 5841µV(±2438µV), in AM 15mg/kg: 3766µV(±1626µV; p<0.05), in DE 15mg/kg: 3423µV(±1892µV p<0.05)]. In rats pretreated with RS the AUC under CRD was 7359µV(±1418µV; p<0.001). Coadministration of AM and RS resulted in an AUC of 6329µV(±1158µV) while in rats treated with RS and DE the AUC again was significantly lower compared to controls [3444µV(±1377µV; p<0.05)]. 5-HT levels were increased in TCA pretreated rats compared to controls. Significantly lower 5-HT levels were found in all rats pretreated with RS (RS; RS+DE; RS+AM).

Conclusions: In contrast to RS administration with consecutively lowered 5-HT serum levels and increased visceral sensitivity, application of AM and DE significantly decrease visceral nociception. While in coadministration with RS antinociceptive capability of AM is abolished, in DE treated animals no alteration in visceral sensitivity can be detected. Our study provides further evidence, that TCAs impact on visceral nociception is only partially modulated by serotonergic mechanisms