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.


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 microV+/-1772 microV). Co-administration of AM and RES resulted in a modest decrease in VMR (5774 microV+/-1953 microV), while in rats treated with RES and DES the VMR again was significantly lower (3446 microV (+/-1347 microV; 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.
Bechmann
Lars P
LP
Department of Gastroenterology, University of Essen, Germany.
Best
Jan
J
Haag
Sebastian
S
Leineweber
Kirsten
K
Gerken
Guido
G
Holtmann
Gerald
G
D000639:Amitriptyline / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage* / Q000494:pharmacology*; D003891:Desipramine / Q000008:administration & dosage / Q000494:pharmacology; D023421:Models, Animal; D009619:Nociceptors / Q000187:drug effects*; D051381:Rats; D012110:Reserpine / Q000008:administration & dosage / Q000494:pharmacology; D012701:Serotonin / Q000097:blood*
D000929:Antidepressive Agents, Tricyclic; D000639:Amitriptyline; D012701:Serotonin; D012110:Reserpine; D003891:Desipramine