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General and Comparative Endocrinology Dec 2021Previously, pheasant motilin was identified as a 22-amino acid peptide with a sequence of FVPFFTQSDI QKMQEKERIK GQ. In the present study, the distribution of pheasant...
Previously, pheasant motilin was identified as a 22-amino acid peptide with a sequence of FVPFFTQSDI QKMQEKERIK GQ. In the present study, the distribution of pheasant motilin mRNA was determined and compared with that of ghrelin, a motilin-related peptide. The effects of pheasant motilin on the cognate gastrointestinal (GI) muscle strips were also examined in an in vitro contraction study. The expression of pheasant motilin mRNA was highest in the small intestine (duodenum, jejunum and ileum), moderate in the colon and very low in the brain, lung, heart, pancreas, esophagus, proventriculus, gizzard and caecum, and this distribution was in contrast with that of ghrelin mRNA. Pheasant motilin caused contraction of the cognate GI tract in a region-dependent manner, similar to chicken motilin. The contraction in the small intestine was large and was not affected by atropine. In contrast, contraction in the proventriculus was small and was decreased by atropine. The crop and colon were insensitive to pheasant motilin. Neither GM109 nor MA2029, mammalian motilin receptor antagonists inhibited the contractions of pheasant motilin. Erythromycin was ineffective in the pheasant ileum, although it caused contraction of the rabbit duodenum. These results indicate that pheasant motilin caused contraction through an action on smooth muscles in the small intestine and an action on enteric cholinergic nerves in the proventriculus. This high responsiveness of the small intestine suggests that motilin is a regulator of small intestinal motility in avians, and the characteristic of the motilin receptor in the pheasant might be different from that in mammals, as is that in chickens.
Topics: Animals; Chickens; Gastrointestinal Motility; Gastrointestinal Tract; Motilin; Muscle Contraction; Rabbits
PubMed: 34506789
DOI: 10.1016/j.ygcen.2021.113897 -
Current Treatment Options in... Dec 2016Chronic unexplained nausea and vomiting (CUNV) refers to a symptom complex defined by nausea and/or vomiting with normal diagnostic testing, including anatomic... (Review)
Review
Chronic unexplained nausea and vomiting (CUNV) refers to a symptom complex defined by nausea and/or vomiting with normal diagnostic testing, including anatomic assessments (including upper endoscopy) and measures of upper gut function (e.g., gastric emptying testing). Nausea and vomiting in this condition are postulated to result from aberrant peripheral or central neurohumoral activity. A substantial subset of patients satisfies this diagnosis as more than half of individuals referred for scintigraphic testing exhibit normal gastric emptying rates. No randomized, placebo-controlled trials of any medication treatment have been performed in CUNV. However, agents with potential therapeutic benefits in CUNV include antiemetic drugs, neuromodulatory treatments which are proposed to act by reducing gastric sensitivity, and medications with prokinetic action to stimulate upper gut propulsion. Recently approved drugs with antiemetic capability include serotonin antagonists with novel modes of delivery and neurokinin antagonists with or without additional serotonergic blocking capabilities. Existing neuroleptics and pain-modifying neuromodulatory therapies with fortuitous antiemetic benefits are being considered for their benefits in this disorder. Furthermore, current investigations will define potential therapeutic actions of agents that stimulate gastric emptying via action on gastroduodenal serotonin, motilin, and ghrelin receptors. This current research may broaden the treatment options for refractory cases of unexplained nausea and vomiting.
PubMed: 27726068
DOI: 10.1007/s11938-016-0110-2 -
Current Gastroenterology Reports Sep 2017The goal of this review is to review the current status of prokinetics and to place it in historical context. Impaired motility and thus propulsion have long been... (Review)
Review
PURPOSE OF REVIEW
The goal of this review is to review the current status of prokinetics and to place it in historical context. Impaired motility and thus propulsion have long been thought to play important roles in the pathogenesis of a number of gastrointestinal disorders including gastroesophageal reflux disease (GERD), gastroparesis, chronic idiopathic pseudo-obstruction, and constipation. Historically, disordered motility was also thought to contribute to a number of functional gastrointestinal disorders such as functional dyspepsia (FD) and irritable bowel syndrome (IBS).
RECENT FINDINGS
As we learn more of the pathophysiology of FD, IBS, GERD, constipation, and gastroparesis, the limitations of a therapeutic strategy based on the stimulation of motility (i.e., the use of a prokinetic) have become apparent and the disappointments of the past explained. The development of prokinetic drugs has also been hampered by the non-selective nature of many of the agents studied to date which resulted in some unexpected side effects. There is still an unmet need for an effective and safe prokinetic, but drug development in this area must be mindful of the challenges of the area and the need for selectivity for a given target receptor.
Topics: Constipation; Dyspepsia; Gastroesophageal Reflux; Gastrointestinal Agents; Gastrointestinal Diseases; Gastrointestinal Motility; Gastroparesis; Humans; Irritable Bowel Syndrome
PubMed: 28887755
DOI: 10.1007/s11894-017-0593-6 -
Current Reviews in Clinical and... 2022Functional gastrointestinal disorders account for at least a third of visits to gastroenterology clinics. Despite pathophysiological complexity, impaired gut motility...
BACKGROUND
Functional gastrointestinal disorders account for at least a third of visits to gastroenterology clinics. Despite pathophysiological complexity, impaired gut motility may be frequently present in these disorders.
INTRODUCTION
Prokinetics are a class of drugs that promote gastrointestinal motility, accelerate transit, and potentially improve digestive symptoms. Several prokinetic agents with a great variety of mechanisms of action are available.
AIM
The purpose of this paper is to update our current knowledge about the efficacy and safety of prokinetics.
METHODS
A literature search on efficacy and safety of prokinetics was carried out using the online databases of Pubmed, Medline, and Cochrane.
RESULTS
Based on the action of different receptors, prokinetics mainly comprise dopamine antagonists, 5HT4 agonists, motilin agonists, ghrelin agonists, and cholinergic agonists. Prokinetics have the potential to improve motility function in all segments of the digestive tract, from the esophagus to the colon. In particular, drug international agencies have approved antidopaminergic metoclopramide for the treatment of gastroparesis and serotoninergic prucalopride for chronic constipation not responsive to traditional laxatives. Arrhythmias by QT prolongation and galactorrhea by prolactin stimulation are the more frequent side effects related to prokinetics use.
CONCLUSION
Old and new prokinetics are effective in ameliorating digestive motility disorders and related symptoms and are widely prescribed. Special attention should be paid to the potential adverse events of these agents.
Topics: Colon; Constipation; Gastrointestinal Diseases; Gastrointestinal Motility; Gastroparesis; Humans
PubMed: 34455950
DOI: 10.2174/2772432816666210805125813 -
Frontiers in Physiology 2021Motilin increases left gastric artery (LGA) blood flow in dogs the endothelial motilin receptor (MLNR). This article investigates the signaling pathways of endothelial...
Motilin increases left gastric artery (LGA) blood flow in dogs the endothelial motilin receptor (MLNR). This article investigates the signaling pathways of endothelial MLNR. Motilin-induced relaxation of LGA rings was assessed using wire myography. Nitric oxide (NO), and cyclic guanosine monophosphate (cGMP) levels were measured using an NO assay kit and cGMP ELISA kit, respectively. Motilin concentration-dependently (EC=9.1±1.2×10M) relaxed LGA rings precontracted with U46619 (thromboxane A receptor agonist). GM-109 (MLNR antagonist) significantly inhibited motilin-induced LGA relaxation and the production of NO and cGMP. N-ethylmaleimide (NEM; G-protein antagonist), U73122 [phospholipase C (PLC) inhibitor], and 2-aminoethyl diphenylborinate [2-APB; inositol trisphosphate (IP) blocker] partially or completely blocked vasorelaxation. In contrast, chelerythrine [protein kinase C (PKC) inhibitor] and H89 [protein kinase A (PKA) inhibitor] had no such effect. Low-calcium or calcium-free Krebs solutions also reduced vasorelaxation. N-nitro-L-arginine methyl ester [L-NAME; nitric oxide synthase (NOS) inhibitor] and ODQ [soluble guanylyl cyclase (sGC) inhibitor] completely abolished vasodilation and synthesis of NO and cGMP. Indomethacin (cyclooxygenase inhibitor), 18α-glycyrrhetinic acid [18α-GA; myoendothelial gap junction (MEGJ) inhibitor], and K channel inhibition through high K concentrations or tetraethylammonium (TEA-Cl; K channel blocker) partially decreased vasorelaxation, whereas glibenclamide (K channel blocker) had no such effect. The current study suggests that motilin-induced LGA relaxation is dependent on endothelial MLNR through the G protein-PLC-IP pathway and Ca influx. The NOS-NO-sGC-cGMP pathway, prostacyclin, MEGJ, and K channels (especially K) are involved in endothelial-dependent relaxation of vascular smooth muscle (VSM) cells.
PubMed: 34777026
DOI: 10.3389/fphys.2021.770430 -
Frontiers in Neuroscience 2023To observe the effects of intrathecal administration of motilin on pain behavior and expression of motilin (MTL)/motilin receptor (MTLR) in the spinal cord of a rat...
AIMS
To observe the effects of intrathecal administration of motilin on pain behavior and expression of motilin (MTL)/motilin receptor (MTLR) in the spinal cord of a rat model of acute incisional pain.
METHODS
An incisional pain model was established in rats using a unilateral plantar incision. The rats were also injected intrathecally with 1, 5, or 25 μg of motilin. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were determined. MTL/MTLR expression in the spinal cord was detected by western blotting and immunofluorescence. The expression of MTL in the spinal cord, stomach, duodenum, and plasma was determined by enzyme-linked immunosorbent assay (ELISA).
RESULTS
Motilin/motilin receptor were detected in the spinal cord. Spinal cord MTL/MTLR expression peaks at 2 h after modeling ( < 0.05) and start to decrease at 24 h ( < 0.05) to almost reach baseline levels at 72 h. The changes in gastric, duodenal, plasma, and spinal cord motilin levels correlated with MWT and TWL (all > 0.82). The intrathecal injection of 1, 5, or 25 μg of motilin could increase the pain threshold of rats with incisional pain within 72 h in a dose-dependent manner.
CONCLUSION
This study showed for the first time that MTL/MTLR are expressed in rats' spinal dorsal horn. Acute pain increased MTL/MTLR expression in the spinal dorsal horn. Also, for the first time, this study showed that motilin intrathecal injection alleviates pain in rat models of acute incisional pain. These results suggest that MTL/MTLR could be a novel target for the management of acute pain.
PubMed: 36816129
DOI: 10.3389/fnins.2023.1104862 -
Clinical Gastroenterology and... Aug 2016This review of the pathophysiologic basis for gastroparesis and recent advances in the treatment of patients with gastroparesis shows that there are several novel... (Review)
Review
This review of the pathophysiologic basis for gastroparesis and recent advances in the treatment of patients with gastroparesis shows that there are several novel approaches to advance treatment of gastroparesis including diet, novel prokinetics, interventions on the pylorus, and novel forms of gastric electrical stimulation. The field of gastroparesis is likely to advance with further studies, with help from a guidance document from the Food and Drug Administration on gastroparesis, and with recent approval of the stable isotope gastric emptying test to ensure eligibility of participants in multicenter trials. Clinical experience and a formal, randomized, controlled trial provide insights on optimizing dietary interventions in patients with gastroparesis. This review addresses the biologic rationale of these different treatments, based on known physiology and pathophysiology of gastric emptying. The novel medications include the motilin agonist, camicinal; 5-HT4 receptor agonists, such as velusetrag; and the ghrelin agonist, relamorelin. New approaches target pylorospasm by stent placement, endoscopic pyloric myotomy, or laparoscopic pyloroplasty. These approaches offer the opportunity to achieve more permanent reduction of resistance to flow at the pylorus over the intrapyloric injection of botulinum toxin, which typically has to be repeated every few months if it is efficacious. A novel device, deployed in porcine stomach, involved per-endoscopic electrical stimulation. These promising approaches require formal, randomized, controlled trials and deployment in patients. The presence of concomitant antral hypomotility may be a significant factor in the responsiveness to interventions at the pylorus.
Topics: Diet Therapy; Electric Stimulation; Gastrointestinal Agents; Gastroparesis; Humans; Surgical Procedures, Operative
PubMed: 26762845
DOI: 10.1016/j.cgh.2015.12.033 -
Endocrine Reviews May 2024Carcinoid syndrome (CS) is a debilitating disease that affects approximately 20% of patients with neuroendocrine neoplasms (NEN). Due to the increasing incidence and... (Review)
Review
Carcinoid syndrome (CS) is a debilitating disease that affects approximately 20% of patients with neuroendocrine neoplasms (NEN). Due to the increasing incidence and improved overall survival of patients with NEN over recent decades, patients are increasingly suffering from chronic and refractory CS symptoms. At present, symptom control is hampered by an incomplete understanding of the pathophysiology of this syndrome. This systematic review is the first to critically appraise the available evidence for the various hormonal mediators considered to play a causative role in CS. Overall, evidence for the putative mediators of CS was scarce and often of poor quality. Based on the available literature, data are only sufficient to agree on the role of serotonin as a mediator of CS-associated diarrhea and fibrosis. A direct role for tachykinins and an indirect role of catecholamines in the pathogenesis of CS is suggested by several studies. Currently, there is insufficient evidence to link histamine, bradykinin, kallikrein, prostaglandins, or motilin to CS. To summarize, available literature only sufficiently appoints serotonin and suggests a role for tachykinins and catecholamines as mediators of CS, with insufficient evidence for other putative mediators. Descriptions of CS should be revised to focus on these proven hormonal associations to be more accurate, and further research is needed into other potential mediators.
Topics: Humans; Malignant Carcinoid Syndrome; Serotonin; Catecholamines; Tachykinins
PubMed: 38038364
DOI: 10.1210/endrev/bnad035 -
International Journal of Molecular... Mar 2019Gastrointestinal motility is regulated by neural factors and humoral factors. Both motilin and ghrelin improve gastrointestinal motility, but many issues remain unclear....
Gastrointestinal motility is regulated by neural factors and humoral factors. Both motilin and ghrelin improve gastrointestinal motility, but many issues remain unclear. We prepared human transgenic (Tg) mice and performed experiments evaluating the effects of motilin, erythromycin (EM), and ghrelin. EM and ghrelin promoted gastric emptying (GE) when administered either peripherally or centrally to Tg mice. Atropine (a muscarinic receptor antagonist) counteracted GE induced by centrally administered EM, but not that induced by peripherally administered EM. The administration of EM in this model promoted the effect of mosapride (a selective serotonin 5-hydroxytryptamine 4 (5-HT4) receptor agonist), and improved loperamide (a μ-opioid receptor agonist)-induced gastroparesis. The level of acyl-ghrelin was significantly attenuated by EM administration. Thus, we have established an animal model appropriate for the evaluation of motilin receptor agonists. These data and the model are expected to facilitate the identification of novel compounds with clinical potential for relieving symptoms of dyspepsia and gastroparesis.
Topics: Animals; Benzamides; Erythromycin; Gastric Emptying; Gastroparesis; Ghrelin; Humans; Loperamide; Male; Mice, Inbred C57BL; Mice, Transgenic; Morpholines; Postprandial Period; RNA, Messenger; Receptors, Gastrointestinal Hormone; Receptors, Ghrelin; Receptors, Neuropeptide; Stomach; Vagus Nerve
PubMed: 30934667
DOI: 10.3390/ijms20071521 -
Frontiers in Neuroscience 2016Feeding is an essential behavior for animals to sustain their lives. Over the past several decades, many neuropeptides that regulate feeding behavior have been... (Review)
Review
Feeding is an essential behavior for animals to sustain their lives. Over the past several decades, many neuropeptides that regulate feeding behavior have been identified in vertebrates. These neuropeptides are called "feeding regulatory neuropeptides." There have been numerous studies on the role of feeding regulatory neuropeptides in vertebrates including birds. Some feeding regulatory neuropeptides show different effects on feeding behavior between birds and other vertebrates, particularly mammals. The difference is marked with orexigenic neuropeptides. For example, melanin-concentrating hormone, orexin, and motilin, which are regarded as orexigenic neuropeptides in mammals, have no effect on feeding behavior in birds. Furthermore, ghrelin and growth hormone-releasing hormone, which are also known as orexigenic neuropeptides in mammals, suppress feeding behavior in birds. Thus, it is likely that the feeding regulatory mechanism has changed during the evolution of vertebrates. This review summarizes the recent knowledge of peptidergic feeding regulatory factors in birds and discusses the difference in their action between birds and other vertebrates.
PubMed: 27853416
DOI: 10.3389/fnins.2016.00485