The brain‐penetrating, orally bioavailable, ghrelin receptor agonist HM01 ameliorates motion‐induced emesis in Suncus murinus (house musk shrew)

Abstract

Background and Purpose HM01, a novel, orally bioavailable, brain‐penetrating agonist of ghrelin receptors, ameliorates emesis in Suncus murinus. This study compared HM01's activity against motion sickness with that of the less brain‐penetrating ghrelin receptor agonist, HM02. Experimental Approach The potential of HM01 and HM02 to relax isolated mesenteric arteries and to increase feeding was investigated. Radio telemetry was used to record gastric slow waves and body temperature. Plethysmography was used to measure respiratory function. HM01 and HM02 were administered p.o. 1 hr prior to provocative motion, and c‐Fos expression in brain sections was assessed. Key Results HM01 and HM02 both relaxed precontracted arteries, yielding EC50 values of 2.5 ± 0.5 and 3.5 ± 0.4 nM respectively. HM01 increased feeding, but HM02 did not. Both compounds caused hypothermia and bradygastria. Motion induced 123 ± 24 emetic events. HM01, but not HM02, reduced motion‐induced emesis by 67.6%. Motion increased c‐Fos expression in the nucleus tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMNV), medial vestibular nucleus (MVe), central nucleus of the amygdala, and paraventricular hypothalamic nucleus (PVH). HM01 alone increased c‐Fos expression in the area postrema, NTS, DMNV, PVH, and arcuate hypothalamic nucleus; HM02 had a similar pattern except it did not increase c‐Fos in the PVH. Both compounds antagonized the motion‐induced increases in c‐Fos expression in the MVe. Conclusions and Implications HM01 is more effective than HM02 in preventing motion‐induced emesis. The difference in potency may relate to activation of ghrelin receptors in the PVH.

Insights Into Acute and Delayed Cisplatin-Induced Emesis From a Microelectrode Array, Radiotelemetry and Whole-Body Plethysmography Study of Suncus murinus (House Musk Shrew)

“…Several studies have shown that respiratory function is disturbed during nausea and interrupted during emesis ( Horn et al, 2016 ; Gavgani et al, 2017 ). Our previous studies in shrews have revealed that provocative motion induces a significant increase in the respiratory rate, concomitant with a reduction in tidal volume ( Tu et al, 2017a ; Tu et al, 2020 ). In the present study, we found that cisplatin treatment of S. murinus caused a reduction in the animals’ respiratory rate, while other parameters remained unchanged.…”

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

“… 129 Compound 61 also promoted motion-induced emesis more effectively than compound 63 in suncus murinus , suggesting that this effect is centrally induced, probably by the activation of GHS-R1a of the paraventricular hypothalamic nucleus. 130 …”

The controversial role of the vagus nerve in mediating ghrelin's actions: gut feelings and beyond

“…In particular, ICV- or intravenously (IV)-injected ghrelin in rats increased the expression of the marker of neuronal activation c-Fos in the DMNV ( Date et al, 2001 , Li et al, 2006 ). Moreover, oral administration of ghrelin analogs increased c-Fos in the DMNV of shrews ( Tu et al, 2020 ), and ICV-injected ghrelin increased phosphorylation of the mammalian target of rapamycin in the DMNV of rats ( Zhang et al, 2013 ). Importantly, GHSR signaling does not specifically recruit any of the referred signaling proteins and, consequently, the referred functional studies may involve indirect actions of ghrelin on the DMNV.…”