Novel mixed NOP/MOP agonist BU08070 alleviates pain and inhibits gastrointestinal motility in mouse models mimicking diarrhea-predominant irritable bowel syndrome symptoms

Abstract

Background The opioid and nociceptin systems play a crucial role in the maintenance of homeostasis in the gastrointestinal (GI) tract. The aim of this study was to characterize the effect of BU08070, a novel mixed MOP/NOP agonist, on mouse intestinal contractility in vitro and GI motility in vivo in physiological conditions and in animal models mimicking symptoms of irritable bowel syndrome (IBS), including diarrhea and abdominal pain. Methods The effect of BU08070 on muscle contractility in vitro was characterized in the ileum and colon. To assess the effect of BU08070 in vivo, the following parameters were assessed: whole GI transit, gastric emptying, geometric center, colonic bead expulsion, fecal pellet output and time to castor oil-induced diarrhea. The antinociceptive activity of BU08070 was characterized in the mustard oil (MO)-induced abdominal pain model and the writhing test, alone and in the presence of MOP and NOP antagonists. Results In vitro, BU08070 (10−10–10−6 M) inhibited colonic and ileal smooth muscle contractions in a concentration-dependent manner. In vivo, BU08070 prolonged the whole GI transit and inhibited colonic bead expulsion. The antitransit and antidiarrheal effect of BU08070 was observed already at the dose of 0.1 mg/kg (i.p.). BU08070 reversed hypermotility and reduced pain in mouse models mimicking IBS-D symptoms. Conclusion Our results suggest that BU08070 has a potential of becoming an efficient drug in IBS-D therapy. Here we also validate mixed NOP/MOP receptor targeting as possible future treatment of functional GI diseases.

Anti-inflammatory effect of dual nociceptin and opioid receptor agonist, BU08070, in experimental colitis in mice

“…Moreover, we observed a decrease in MPO activity after BU08070 treatment and this effect was mediated principally by MOP receptors, but not NOP receptors. These findings elegantly support the concept that the activation of opioid and NOP receptors induces anti-inflammatory response during intestinal inflammation and are in line with our earlier observations for classical and non-classical NOP and MOP receptor agonists (Sobczak et al, 2014). …”

“…The attenuation of disease progression was correlated with decreased production of pro-inflammatory cytokines in the colon, including IL-1β, IL-6, and TNF-α. In contrast, in our earlier study we showed that SCH 221510, a selective NOP receptor agonist, induced anti-inflammatory response in TNBS-induced colitis in mice in a NOP receptor-reversible manner (Sobczak et al, 2014). We also observed a decrease in the relative NOP receptor mRNA expression in biopsies collected from IBD patients in comparison with healthy subjects.…”

“…To assess the antinociceptive effect of BU08070 in mice with acute colitis, intestinal inflammation was induced by TNBS instillation four days prior to proper experiment (Sobczak et al, 2014). On day 4, animals were divided into two groups: BU08070-treated and vehicle-treated.…”

“…In our previous studies we showed that an analogue of buprenorphine, BU08070, displayed higher binding affinity to MOP and NOP receptors in comparison with parent compound. BU08070 was active in the GI tract and exerted antinociceptive effect in the mouse models of visceral pain (Cami-Kobeci et al, 2011; Sobczak et al, 2014). The aim of our study was to assess the effect of BU08070, a buprenorphine analogue with dual activity at NOP and MOP receptors, on the severity of intestinal inflammation in the mouse model of TNBS-induced colitis and to determine its mechanism of action.…”

Role of Principal Ionotropic and Metabotropic Receptors in Visceral Pain

“…Moreover, the same group has previously reported an antinociceptive effect of the same drug when orally administered in a mouse model of trinitrobenzene sulfonic acid-induced colitis. 89 In vitro afferent recordings from mouse splanchnic high-threshold nociceptors from mice with colonic inflammation we found that asimadoline (peripherally restricted selective KOR agonist) dose-dependently inhibited colonic nociceptors. Furthermore, asimadoline also dose dependently inhibited colonic nociceptors from chronic visceral hypersensitivity, an effect that was prevented by the prior application of a KOR antagonist.…”