Anti-emetic drug maropitant induces intestinal motility disorder but not anti-inflammatory action in mice

Maropitant is a selective neurokinin 1 receptor (NK1R) antagonist that is clinically used as anti-emetic drugs (Cerenia® by Pfizer Animal Health, Madison, NJ, U.S.A.) for dog [12]. NK1R is expressed in emetic center and chemoreceptor trigger zone (CTZ). Maropitant blocks the binding of substance P (SP), a ligand of NK1R, to the receptor in emetic center and CTZ, resulting in the prevention of emesis. NK1R is also expressed in many types of cells in intestine. NK1R has been identified on smooth muscle cells, ascending and descending neurons, interstitial cells of Cajal (ICC) at deep muscular plexus and myeloid cells of the villi [14, 19]. In mice, it has been reported that SP / NK1R signaling is involved in non-adrenergic and non-cholinergic neuronally mediated contractions in circular smooth muscle in intestine [4]. On the other hand, SP also stimulates ICC pacemaker activity via NK1R [2, 19]. It is possible that pharmacological substrates for NK1R can modulate gastrointestinal motility. Ligands for NKRs are tachykinin peptides, including SP, neruokinin A-B, hemokinin-1 and endokinins A-D. SP is primarily found in enteric neuron, but SP is also secreted by inflammatory stimuli from many kinds of immune reactive cells, such as lymphocytes, eosinophils, macrophages and dendritic cells [8]. Secreted SP from neuronal cells and immune cells is considered to accelerate inflammation in an autocrine and/or paracrine manner [6, 15]. So, tachykinin peptides are considered as important inflammatory mediators in gastrointestinal and inflammatory diseases. Taken together, it is hypothesized that maropitant may inhibit gastrointestinal motility and inflammatory responses. Based on these backgrounds, we investigated the effects of maropitant on intestinal motility in ex vivo and in vivo assays and leukocytes infiltration into the inflamed muscle layer in post-operative ileus (POI) model mice.