Serotoninergic and non-serotoninergic effects of two tricyclic antidepressants on visceral nociception in a rat model

Objective. Tricyclic antidepressants (TCAs) are well established in the treatment of patients with irritable bowel syndrome (IBS). The effects are believed to be linked to serotoninergic antinociceptive properties, but data on the antinociceptive effects of various TCAs with variable serotoninergic and non-serotoninergic properties have not been investigated. The aim of this study was to compare the antinociceptive effects of different TCAs. Material and methods. Colorectal distension (CRD) using a barostat device was carried out in rats and the visceromotor response (VMR) to CRD was quantified by abdominal wall electromyography. Prior to CRD, saline (control), amitriptyline (AM), desipramine (DES), reserpine (RES) or a combination of TCAs and RES (AM + RES or DES + RES) was applied intraperitoneally. Serum 5-HT levels were determined using high-performance liquid chromatography (HPLC). RES was used to antagonize the serotoninergic actions of TCAs in order to discriminate between these effects and others. Results. Both TCAs decreased the VMR compared to placebo. After RES application without TCAs, the VMR was increased compared to controls (6403 µV±1772 µV). Co-administration of AM and RES resulted in a modest decrease in VMR (5774 µV±1953 µV), while in rats treated with RES and DES the VMR again was significantly lower (3446 µV (±1347 µV; p <0.05)). 5-HT levels were higher in TCA pretreated rats than those in controls and significantly lower 5-HT levels were found in all rats pretreated with RES. Conclusions. AM and DES have antinociceptive properties while RES is pro-nociceptive. The antinociceptive effects of DES are not abolished by RES pretreatment, while AM only attenuates the pro-nociceptive effects of RES. The non-serotoninergic properties of TCAs substantially contribute to the differences in the antinococeptive effects of various TCAs.Lars P. Bechmann, Jan Best, Sebastian Haag, Kirsten Leinewebe, Guido Gerken and Gerald Holtman