Inhibition of Phosphodiesterase Type 4 Decreases Stress-Induced Defecation in Rats and Mice

Abstract

Background/Aims: Phosphodiesterase type 4 (PDE4) has been previously shown to regulate colonic contractile activity in vitro. In this study, the effects of PDE4 inhibition were assessed in a model of stress-induced defecation previously demonstrated to be due to increased colonic transit/evacuation. Methods: Rats were individually placed in a mild restraint cage and placed into a 12°C environment (cold-restraint stress) for 60 min. Mice received restraint (only) stress at room temperature for 30 min. Loperamide (positive control compound) or two different PDE4 inhibitors (rolipram and roflumilast) were administered orally at several doses to the rodents 1 h before stress began. Vehicle alone was administered for comparison. The number of fecal pellets expelled during stress (fecal pellet output), total fecal pellet wet weight and total fecal water content were measured. Results: Loperamide produced a dose-related decrease (ID₅₀s in mg/kg) in fecal pellet output (rat = 7.4, mouse = 0.7) and significantly decreased fecal wet weight (72.9%) and decreased fecal percent water content (9.4%). The two PDE4 inhibitors produced a similar dose-related inhibition of fecal pellet output. Rolipram exhibited ID₅₀s in rat and mouse of 14.1 and 27.1, respectively. Rolipram significantly decreased fecal wet weight (58.8%) but increased fecal percent water content (15.0%). For roflumilast, ID₅₀s were 24.2 mg/kg and 12.4 in the rat and mouse, respectively. Although roflumilast also significantly (p < 0.05) decreased fecal wet weight (47.2%), it did not significantly increase fecal percent water content. Conclusions: These data indicate that PDE4 inhibition is effective in reducing rodent stress-induced defecation, provides the first functional data on a potential role for PDE4 activity in the colonic evacuation response to stress, and indicates the potential utility of PDE4 inhibitors in functional bowel disease such as irritable bowel syndrome requires further evaluation.

Aminophylline suppresses stress-induced visceral hypersensitivity and defecation in irritable bowel syndrome

“…Therefore, confirmation that a selective PDE4 activator or a selective A 2B AR agonist can inhibit the ameliorating effect of aminophylline is warranted. Furthermore, these results are consistent with those of previous reports showing that A 2B AR-knockout mice have decreased stool frequency32 and that inhibition of PDE4 suppresses stress-induced defecation35. Nevertheless, they do not agree with the finding by Antonioli et al .…”

“…Further, activation of A 1 ARs in the spinal cord has an analgesic effect34. On the other hand, it has been reported that inhibition of PDE4 suppresses stress-induced defecation35. These results suggest that aminophylline (theophylline) may affect visceral hypersensitivity and stress-induced defecation in IBS-D patients and animal models either positively or negatively; however, no study to date has investigated these effects.…”

Resistance to Early-Life Stress in Mice: Effects of Genetic Background and Stress Duration

“…Although somewhat surprising, we found similar results in BALB/c mice following social defeat stress (Savignac and Cryan, unpublished). The opposite effect was expected, as exposure to a novel environment increases fecal output (Barone et al, 2008; Wang et al, 2010). These data suggest mice may have displayed a decrease in colonic motility which would be relevant to IBS patients displaying a constipation phenotype, which has not been established in traditional IBS mouse models (Bercik et al, 2004; Kimball et al, 2005; Coates et al, 2006).…”

“…The apparatus was a gray plastic open arena without any bedding (40 cm × 30 cm × 25 cm, L  ×  W  ×  H ). Mice were allowed 10-min free exploration in the box, behavior was recorded using a video camera and the number of fecal pellets in the arena was counted as an index of anxiety (Barone et al, 2008). For data analysis, the arena was divided into 16 equal areas with the 4 central ones constituting the central zone.…”

Impact of germline and somatic missense variations on drug binding sites

“…Roflumilast, another example, shows anti-inflammatory and anti-modulatory effects in the pulmonary system by selectively inhibiting phosphodiesterase-4. 76 Amino acid–drug binding data retrieved from PDB show the binding between cAMP-specific 3',5'-cyclic phosphodiesterase 4D (PDE4D) and Roflumilast. Our paralogs survey shows that paralogs PDE4A, PDE4B and PDE4C are potential alternative target proteins.…”