Motilin: towards a new understanding of the gastrointestinal neuropharmacology and therapeutic use of motilin receptor agonists

Abstract

The gastrointestinal hormone motilin has been known about for >40 years, but after identification of its receptor and subsequent development of new tools and methods, a reappraisal of its actions is required. Firstly, it is important to note that motilin and ghrelin receptors are members of the same family (similar genomic organization, gastrointestinal distribution and abilities to stimulate gastrointestinal motility), yet each fails to recognize the ligand of the other; and whereas ghrelin and ghrelin receptors are widespread outside the gastrointestinal tract, motilin and its receptors are largely restricted to the gastrointestinal tract. Secondly, although some studies suggest motilin has activity in rodents, most do not, and receptor pseudogenes exist in rodents. Thirdly, motilin preferentially operates by facilitating enteric cholinergic activity rather than directly contracting the muscle, despite the relatively high expression of receptor immunoreactivity in muscle. This activity is ligand-dependent, with short-lasting actions of motilin contrasting with longer-lasting actions of the non-selective and selective motilin receptor agonists erythromycin and GSK962040. Finally, the use of erythromycin (also an antibiotic drug) to treat patients requiring acceleration of gastric emptying has led to concerns over safety and potential exacerbation of antibiotic resistance. Replacement motilin receptor agonists derived from erythromycin (motilides) have been unsuccessful. New, non-motilide, small molecule receptor agonists, designed to minimize self-desensitization, are now entering clinical trials for treating patients undergoing enteral feeding or with diabetic gastroparesis. Thus, for the translational pharmacologist, the study of motilin illustrates the need to avoid overreliance on artificial systems, on structural information and on animal studies.

Linked articles: This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7.

Keywords: gastrointestinal; ghrelin; motilin; neuropharmacology; translational sciences.

Figure 1

Data illustrating some major issues surrounding the interpretation and translation of in vitro studies with motilin. (A) Activation by motilin and erythromycin of recombinant human motilin receptors expressed in CHO cells, measuring changes in intracellular Ca²⁺. The t_½ values represent the times taken for the response to decline by 50% and are measured in s. Data are given as the means ± SEM of three repeat experiments. (B) Expression of motilin receptor immunoreactivity in human gastric antrum (stained in red) showing distribution of the receptor to the longitudinal and circular muscle layers of the antrum, and to the myenteric plexus; illustrations are ×10 and ×25. (C) Facilitation by motilin and erythromycin of cholinergically-mediated contractions of human gastric antrum circular muscle, showing differences in the duration of facilitation longer than those measured in the recombinant receptor studies. Each trace shows the actions of a submaximally effective concentration. For details on experimental methods (immunohistochemistry and human stomach), see Broad et al. (2012).