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

Abstract

Pharmacological therapy for irritable bowel syndrome (IBS) has not been established. In order to find candidate drugs for IBS with diarrhea (IBS-D), we screened a compound library of drugs clinically used for their ability to prevent stress-induced defecation and visceral hypersensitivity in rats. We selected the bronchodilator aminophylline from this library. Using a specific inhibitor for each subtype of adenosine receptors (ARs) and phosphodiesterases (PDEs), we found that both A2BARs and PDE4 are probably mediated the inhibitory effect of aminophylline on wrap restraint stress (WRS)-induced defecation. Aminophylline suppressed maternal separation- and acetic acid administration-induced visceral hypersensitivity to colorectal distension (CRD), which was mediated by both A2AARs and A2BARs. We propose that aminophylline is a candidate drug for IBS-D because of its efficacy in both of stress-induced defecation and visceral hypersensitivity, as we observed here, and because it is clinically safe.

Ameliorative effect of chlorpromazine hydrochloride on visceral hypersensitivity in rats: possible involvement of 5‐HT2A receptor

“…Previously, in a phenotypic screening, we identified aminophylline as a drug that suppressed visceral sensitivity response to repeated CRD. Aminophylline suppressed stress‐induced visceral hypersensitivity by inhibiting adenosine A 2 receptors (Asano et al, ). In the same screen, chlorpromazine showed similar effects.…”

“…VMR to CRD was monitored as described previously (Asano et al, ). Briefly, rats were deeply anaesthetized with an intraperitoneal injection of mixture of medetomidine chloride (0.5 mg·kg −1 ), midazolam (2.5 mg·kg −1 ) and butorphanol tartrate (2.5 mg·kg −1 ).…”

“…We previously screened a compound library of clinically available drugs for their ability to prevent the visceral pain response to noxious CRD (Asano et al, ) and identified aminophylline, a bronchodilator, as a potential candidate. As chlorpromazine strongly suppressed visceral sensitivity to noxious CRD in the same phenotypic screen, it was also considered a candidate drug for abdominal pain.…”

Toward an effective peripheral visceral analgesic: responding to the national opioid crisis

“…Adenosine's role in diverse enteric functions and disease processes are extensively reviewed elsewhere (6,7). Recent data show that, in rat models of IBS (based on stress such as maternal separation or wraprestraint stress), the A 2B receptor antagonist aminophylline reduced visceral pain as well as colonic propulsion (9).…”

A2B adenosine receptor inhibition by the dihydropyridine calcium channel blocker nifedipine involves colonic fluid secretion

“…Recently, we reported that blockade of the A 2B receptor could be beneficial for diarrhoea-predominant IBS 8 . Inhibition of the receptor by pharmacological agents ameliorated colonic hypersensitivity and stress-induced defecation in rodent models of IBS.…”