BackgroundIn most animal species, opioids alter colonic motility via the inhibition of excitatory... more BackgroundIn most animal species, opioids alter colonic motility via the inhibition of excitatory enteric motor neurons. The mechanisms by which opioids alter human colonic motility are unclear. The aim of this study was to describe the effects of loperamide on neuromuscular function in the human colon.MethodsTissue specimens of human colon from 10 patients undergoing an anterior resection were divided into three inter‐taenial circular muscle strips. Separate organ baths were used to assess: (1) excitatory transmission (selective blockade of inhibitory transmission: L‐NOARG/MRS2179); (2) inhibitory transmission (selective blockade of excitatory transmission: hyoscine hydrobromide); and (3) a control bath (no drug additions). Neuromuscular function was assessed using force transducer recordings and electrical field stimulation (EFS; 20 V, 10 Hz, 0.5 ms, 10 s) prior to and following loperamide and naloxone.Key ResultsIn human preparations with L‐NOARG/MRS2179, loperamide had no signif...
American Journal of Physiology-Gastrointestinal and Liver Physiology
The colonic motor complex (CMC) initiates propulsion in guinea pig colon. Here, CMCs evoked by an... more The colonic motor complex (CMC) initiates propulsion in guinea pig colon. Here, CMCs evoked by an intraluminal pellet were restored during nicotinic receptor blockade by pharmacological agents that directly or indirectly enhance intrinsic primary afferent neuron (IPAN) excitability. IPANs are the only enteric neuron in colon that contain CGRP. Blocking CGRP receptors decreased CMC frequency, implicating their role in CMC initiation. The results support a role for IPANs in the initiation of CMCs.
BackgroundPostoperative ileus is common and is a major clinical problem. It has been widely studi... more BackgroundPostoperative ileus is common and is a major clinical problem. It has been widely studied in patients and in experimental models in laboratory animals. A wide variety of treatments have been tested to prevent or modify the course of this disorder.PurposeThis review draws together information on animal studies of ileus with studies on human patients. It summarizes some of the conceptual advances made in understanding the mechanisms that underlie paralytic ileus. The treatments that have been tested in human subjects (both pharmacological and non‐pharmacological) and their efficacy are summarized and graded consistent with current clinical guidelines. The review is not intended to provide a comprehensive overview of ileus, but rather a general understanding of the major clinical problems associated with it, how animal models have been useful to elucidate key mechanisms and, finally, some perspectives from both scientists and clinicians as to how we may move forward with this...
Hypothesis / aims of study Sensory stimuli within the bladder are detected by spinal afferent neu... more Hypothesis / aims of study Sensory stimuli within the bladder are detected by spinal afferent neurons, whose cell bodies lie in dorsal root ganglia (DRG). Unmyelinated C fibres and thinly myelinated Ad axons that project (i) via the sacral-pelvic nerves, and have cell bodies in L6 and S1 DRG or (ii) via lumbar-hypogastric nerves, with their cell bodies primarily in L1-L2 DRG. In functional electrophysiological studies four major classes of sensory neurons were identified in the mouse bladder: (i) low threshold stretch-sensitive muscular and (ii) muscular-mucosal; (iii) stretch-insensitive mucosal and (iv) so-called serosal afferents [1]. In the urinary bladder, the terminal endings of spinal afferents that detect noxious and innocuous stimuli have never been identified in any species.
Soft faecal material is transformed into discrete, pellet‐shaped faeces at the colonic flexure. H... more Soft faecal material is transformed into discrete, pellet‐shaped faeces at the colonic flexure. Here, analysis of water content in natural faecal material revealed a decline from cecum to rectum without significant changes at the flexure. Thus, pellet formation is not explained by changes in viscosity alone. We then used video imaging of colonic wall movements with electromyography in isolated preparations containing guinea‐pig proximal colon, colonic flexure and distal colon. To investigate the pellet formation process, the colonic segments were infused with artificial contents (Krebs solution and 4–6% methylcellulose) to simulate physiological faecal content flow. Remarkably, pellet formation took place in vitro, without extrinsic neural inputs. Infusion evoked slowly propagating neurogenic contractions, the proximal colon migrating motor complexes (∼0.6 cpm), which initiated pellet formation at the flexure. Lesion of the flexure, but not the proximal colon, disrupted the formatio...
BackgroundThe enteric nervous system contains multiple classes of neurons, distinguishable by mor... more BackgroundThe enteric nervous system contains multiple classes of neurons, distinguishable by morphology, immunohistochemical markers, and projections; however, specific combinations differ between species. Here, types of enteric neurons in human colon were characterized immunohistochemically, using retrograde tracing combined with multiple labeling immunohistochemistry, focussing on non‐motor neurons.MethodsThe fluorescent carbocyanine tracer, DiI, was applied to the myenteric plexus in ex vivo preparations, filling neurons projecting within the plexus. Limits of projection lengths of motor neurons were established, allowing them to be excluded from the analysis. Long ascending and descending interneurons were then distinguished by labeling for discriminating immunohistochemical markers: calbindin, calretinin, enkephalin, 5‐hydroxytryptamine, nitric oxide synthase, and substance P. These results were combined with a previous published study in which nitric oxide synthase and cholin...
BackgroundIn most animal species, opioids alter colonic motility via the inhibition of excitatory... more BackgroundIn most animal species, opioids alter colonic motility via the inhibition of excitatory enteric motor neurons. The mechanisms by which opioids alter human colonic motility are unclear. The aim of this study was to describe the effects of loperamide on neuromuscular function in the human colon.MethodsTissue specimens of human colon from 10 patients undergoing an anterior resection were divided into three inter‐taenial circular muscle strips. Separate organ baths were used to assess: (1) excitatory transmission (selective blockade of inhibitory transmission: L‐NOARG/MRS2179); (2) inhibitory transmission (selective blockade of excitatory transmission: hyoscine hydrobromide); and (3) a control bath (no drug additions). Neuromuscular function was assessed using force transducer recordings and electrical field stimulation (EFS; 20 V, 10 Hz, 0.5 ms, 10 s) prior to and following loperamide and naloxone.Key ResultsIn human preparations with L‐NOARG/MRS2179, loperamide had no signif...
American Journal of Physiology-Gastrointestinal and Liver Physiology
The colonic motor complex (CMC) initiates propulsion in guinea pig colon. Here, CMCs evoked by an... more The colonic motor complex (CMC) initiates propulsion in guinea pig colon. Here, CMCs evoked by an intraluminal pellet were restored during nicotinic receptor blockade by pharmacological agents that directly or indirectly enhance intrinsic primary afferent neuron (IPAN) excitability. IPANs are the only enteric neuron in colon that contain CGRP. Blocking CGRP receptors decreased CMC frequency, implicating their role in CMC initiation. The results support a role for IPANs in the initiation of CMCs.
BackgroundPostoperative ileus is common and is a major clinical problem. It has been widely studi... more BackgroundPostoperative ileus is common and is a major clinical problem. It has been widely studied in patients and in experimental models in laboratory animals. A wide variety of treatments have been tested to prevent or modify the course of this disorder.PurposeThis review draws together information on animal studies of ileus with studies on human patients. It summarizes some of the conceptual advances made in understanding the mechanisms that underlie paralytic ileus. The treatments that have been tested in human subjects (both pharmacological and non‐pharmacological) and their efficacy are summarized and graded consistent with current clinical guidelines. The review is not intended to provide a comprehensive overview of ileus, but rather a general understanding of the major clinical problems associated with it, how animal models have been useful to elucidate key mechanisms and, finally, some perspectives from both scientists and clinicians as to how we may move forward with this...
Hypothesis / aims of study Sensory stimuli within the bladder are detected by spinal afferent neu... more Hypothesis / aims of study Sensory stimuli within the bladder are detected by spinal afferent neurons, whose cell bodies lie in dorsal root ganglia (DRG). Unmyelinated C fibres and thinly myelinated Ad axons that project (i) via the sacral-pelvic nerves, and have cell bodies in L6 and S1 DRG or (ii) via lumbar-hypogastric nerves, with their cell bodies primarily in L1-L2 DRG. In functional electrophysiological studies four major classes of sensory neurons were identified in the mouse bladder: (i) low threshold stretch-sensitive muscular and (ii) muscular-mucosal; (iii) stretch-insensitive mucosal and (iv) so-called serosal afferents [1]. In the urinary bladder, the terminal endings of spinal afferents that detect noxious and innocuous stimuli have never been identified in any species.
Soft faecal material is transformed into discrete, pellet‐shaped faeces at the colonic flexure. H... more Soft faecal material is transformed into discrete, pellet‐shaped faeces at the colonic flexure. Here, analysis of water content in natural faecal material revealed a decline from cecum to rectum without significant changes at the flexure. Thus, pellet formation is not explained by changes in viscosity alone. We then used video imaging of colonic wall movements with electromyography in isolated preparations containing guinea‐pig proximal colon, colonic flexure and distal colon. To investigate the pellet formation process, the colonic segments were infused with artificial contents (Krebs solution and 4–6% methylcellulose) to simulate physiological faecal content flow. Remarkably, pellet formation took place in vitro, without extrinsic neural inputs. Infusion evoked slowly propagating neurogenic contractions, the proximal colon migrating motor complexes (∼0.6 cpm), which initiated pellet formation at the flexure. Lesion of the flexure, but not the proximal colon, disrupted the formatio...
BackgroundThe enteric nervous system contains multiple classes of neurons, distinguishable by mor... more BackgroundThe enteric nervous system contains multiple classes of neurons, distinguishable by morphology, immunohistochemical markers, and projections; however, specific combinations differ between species. Here, types of enteric neurons in human colon were characterized immunohistochemically, using retrograde tracing combined with multiple labeling immunohistochemistry, focussing on non‐motor neurons.MethodsThe fluorescent carbocyanine tracer, DiI, was applied to the myenteric plexus in ex vivo preparations, filling neurons projecting within the plexus. Limits of projection lengths of motor neurons were established, allowing them to be excluded from the analysis. Long ascending and descending interneurons were then distinguished by labeling for discriminating immunohistochemical markers: calbindin, calretinin, enkephalin, 5‐hydroxytryptamine, nitric oxide synthase, and substance P. These results were combined with a previous published study in which nitric oxide synthase and cholin...
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Papers by Simon Brookes