The effects of loperamide on excitatory and inhibitory neuromuscular function in the human colon

Heitmann, Paul T.; Keightley, Lauren J.; Wiklendt, Lukasz; Wattchow, David; Brookes, Simon Jonathan; Spencer, Nick J.; Costa, Marcello; Dinning, Phil G.

doi:10.1111/nmo.14442

Cited by 5 publications

(4 citation statements)

References 48 publications

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“…Likewise, in healthy isolated tenia coli muscle, loperamide decreased the release of acetylcholine produced by electrical field stimulation ( Burleigh, 1988 ). A recent report using human inter-tenia circular muscle strips also indicates that loperamide had no direct effect on neuromuscular function supporting an action primarily on enteric neurons ( Heitmann et al, 2022 ). In the clinical setting, loperamide is used for the treatment of acute diarrhea at the therapeutic doses of 2–4 mg/subject ( Vearrier and Grundmann, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

New insight on the enteric cholinergic innervation of the pig colon by central and peripheral nervous systems: reduction by repeated loperamide administration

Yuan

Li²,

Million³

et al. 2023

Front. Neurosci.

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IntroductionThe central and peripheral nervous systems provide cholinergic innervation in the colon. The ability to assess their neuroanatomical distinctions is still a challenge. The pig is regarded as a relevant translational model due to the close similarity of its enteric nervous system (ENS) with that of human. Opioid-induced constipation is one of the most common side effects of opioid therapy.MethodsWe developed an approach to differentiate the central and peripheral cholinergic innervation of the pig colon using double immunolabeling with a novel mouse anti-human peripheral type of choline acetyltransferase (hpChAT) antibody combined with a rabbit anti-common type of ChAT (cChAT) antibody, a reliable marker of cholinergic neurons in the central nervous system. We examined their spatial configurations in 3D images of the ENS generated from CLARITY-cleared colonic segments. The density was quantitated computationally using Imaris 9.7. We assessed changes in the distal colon induced by daily oral treatment for 4 weeks with the μ opioid receptor agonist, loperamide (0.4 or 3 mg/kg).ResultsThe double labeling showed strong cChAT immunoreactive (ir) fibers in the cervical vagus nerve and neuronal somata and fibers in the ventral horn of the sacral (S2) cord while hpChAT immunoreactivity was visualized only in the ENS but not in the vagus or sacral neural structures indicating the selectivity of these two antibodies. In the colonic myenteric plexus, dense hpChAT-ir neurons and fibers and varicose cChAT-ir fibers surrounding hpChAT-ir neurons were simultaneously visualized in 3D. The density of cChAT-ir varicose fibers in the outer submucosal plexus of both males and females were higher in the transverse and distal colon than in the proximal colon and in the myenteric plexus compared to the outer submucosal plexus and there was no cChAT innervation in the inner submucosal plexus. The density of hpChAT in the ENS showed no segmental or plexus differences in both sexes. Loperamide at the highest dose significantly decreased the density hpChAT-ir fibers + somata in the myenteric plexus of the distal colon.DiscussionThese data showed the distinct density of central cholinergic innervation between myenteric and submucosal plexuses among colonic segments and the localization of cChAT-ir fibers around peripheral hpChAT neurons in 3D. The reduction of cholinergic myenteric innervation by chronic opiate treatment points to target altered prokinetic cholinergic pathway to counteract opiate constipation.

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Section: Discussionmentioning

confidence: 99%

New insight on the enteric cholinergic innervation of the pig colon by central and peripheral nervous systems: reduction by repeated loperamide administration

Yuan

Li²,

Million³

et al. 2023

Front. Neurosci.

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“…Conversely, pharmacological blockade of inhibitory transmission during electrical stimulations reveals the actions of excitatory motor neurons. 15,16 Inhibitory transmission can be blocked by nitrergic and purinergic antagonists such as L-NOARG & MRS2179 17,18 suggesting that inhibition is mediated by both nitric oxide and purines.…”

Section: Small Muscle Stripsmentioning

confidence: 99%

“…Cholinergic antagonists do not entirely suppress stimulus‐evoked contractions however, due to the presence of non‐cholinergic excitatory transmitters including Substance P and other tachykinins. Conversely, pharmacological blockade of inhibitory transmission during electrical stimulations reveals the actions of excitatory motor neurons 15,16 . Inhibitory transmission can be blocked by nitrergic and purinergic antagonists such as L‐NOARG & MRS2179 17,18 suggesting that inhibition is mediated by both nitric oxide and purines.…”

Section: Smooth Musclementioning

confidence: 99%

From the organ bath to the whole person: a review of human colonic motility

Wattchow,

Brookes,

Spencer

et al. 2023

ANZ Journal of Surgery

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Motor function of the colon is essential for health. Our current understanding of the mechanisms that underlie colonic motility are based upon a range of experimental techniques, including molecular biology, single cell studies, recordings from muscle strips, analysis of part or whole organ ex vivo through to in vivo human recordings. For the surgeon involved in the clinical management of colonic conditions this amounts to a formidable volume of material. Here, we synthesize the key findings from these various experimental approaches so that surgeons can be better armed to deal with the complexities of the colon.

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“…In addition, opioids can disturb BA metabolism, destroy the intestinal barrier, and affect intestinal motility [ 28 ]. Moreover, activating opioid receptors in the intestine can directly affect intestinal motility, as has been demonstrated for loperamide [ 29 , 30 ].…”

Section: Changes In the Gut Microbiota And Intestinal Motility After ...mentioning

confidence: 99%

Effect of the gut microbiota and their metabolites on postoperative intestinal motility and its underlying mechanisms

et al. 2023

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Gut microbiota is closely related to human health and disease because, together with their metabolites, gut microbiota maintain normal intestinal peristalsis. The use of antibiotics or opioid anesthetics, or both, during surgical procedures can lead to dysbiosis and affect intestinal motility; however, the underlying mechanisms are not fully known. This review aims to discuss the effect of gut microbiota and their metabolites on postoperative intestinal motility, focusing on regulating the enteric nervous system, 5-hydroxytryptamine neurotransmitter, and aryl hydrocarbon receptor.

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The effects of loperamide on excitatory and inhibitory neuromuscular function in the human colon

Cited by 5 publications

References 48 publications

New insight on the enteric cholinergic innervation of the pig colon by central and peripheral nervous systems: reduction by repeated loperamide administration

New insight on the enteric cholinergic innervation of the pig colon by central and peripheral nervous systems: reduction by repeated loperamide administration

From the organ bath to the whole person: a review of human colonic motility

Effect of the gut microbiota and their metabolites on postoperative intestinal motility and its underlying mechanisms

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