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PubMed2002

Modulation of the release of endogenous adenosine by cannabinoids in the myenteric plexus-longitudinal muscle preparation of the guinea-pig ileum.

1. Interactions between the cannabinoid system and the adenosine system were investigated in the myenteric plexus-longitudinal muscle (MPLM) of the guinea-pig ileum. 2. Electrically-evoked contractions of the MPLM were inhibited in a concentration dependent manner by exogenous adenosine and the adenosine receptor agonist 2-chloroadenosine. These inhibitory effects were reversed by the selective A(1) receptor antagonist DPCPX (20 nM). 3. Preincubation of the MPLM with the cannabinoid receptor agonist CP55,940 (1 nM) or the endogenous cannabinoid ligand anandamide caused a significant leftward shift in the concentration-effect curves to adenosine and 2-chloroadenosine. 4. Electrically-evoked contractions of the MPLM were inhibited in a concentration dependent manner by the adenosine uptake inhibitor dipyridamole. This inhibition was reversed by DPCPX (20 nM). 5. Pretreatment with CP55,940 (1 nM) or anandamide (10 microM) significantly reduced the inhibition produced by dipyridamole, an effect which was completely reversed by the selective CB(1) receptor ligand SR141716 (100 nM). 6. Electrically evoked adenosine release, measured in real time by means of adenosine-specific biosensors, was inhibited by CP55,940 (10 nM). This inhibition was blocked when CP55,940 was applied in the presence of SR141716 (100 nM). 7. These results confirm the presence of presynaptic CB(1) and A(1) receptors in the guinea-pig MPLM, and suggest that CB(1) receptor stimulation reduces electrically-evoked adenosine release. Overall the data raise the possibility that the cannabinoid system plays a role in the modulation of adenosine transmission in the MPLM.

Adenosine↗

PubMed1985

Effects of chronic treatment with atypical neuroleptics on the biosynthesis and release of opioid peptides in guinea-pig ileum.

The guinea-pig ileum myenteric plexus is known to contain opioid peptides, which can be released by electric stimulation at high frequency. Haloperidol, a classic neuroleptic drug, increases the biosynthesis and release of endogenous opioid peptides from the myenteric plexus. In the present work we have examined the effects of chronic treatment with sulpiride and clozapine, two atypical neuroleptics, on the release of these peptides in the myenteric plexus of guinea-pig ileum. Both neuroleptics, administered over a period of 7 days, produced an increase of the inhibitory response obtained by electrical stimulation at 10 Hz of the ileum myenteric plexus-longitudinal muscle preparation. The inhibitory response was reversed by the specific opioid antagonist naloxone, which suggest that the increase in the inhibitory response produced by blocking the dopaminergic receptors is mediated by an increase in the release of opioid peptides. When sulpiride- or clozapine-treated guinea-pigs received cycloheximide (an inhibitor of peptide biosynthesis) there was a significant decrease of the inhibitory response, which indicates that neuroleptics produced an increase of the synthesis of opioid peptides in the ileum myenteric plexus. These results reveal a possible influence of the dopaminergic system on the biological turnover of these peptides.

Animals↗

PubMed1994

Nitric oxide synthase immunoreactivity in the enteric nervous system of the developing human digestive tract.

We have investigated indirectly the presence of nitric oxide in the enteric nervous system of the digestive tract of human fetuses and newborns by nitric oxide synthase (NOS) immunocytochemistry and nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) histochemistry. In the stomach, NOS immunoactivity was confined to the myenteric plexus and nerve fibres in the outer smooth musculature; few immunoreactive nerve cell bodies were found in ganglia of the outer submucous plexus. In the pyloric region, a few nitrergic perikarya were seen in the inner submucous plexus and some immunoreactive fibers were found in the muscularis mucosae. In the small intestine, nitrergic neurons clustered just underneath or above the topographical plane formed by the primary nerve strands of the myenteric plexus up to the 26th week of gestation, after which stage, they occurred throughout the ganglia. Many of their processes contributed to the dense fine-meshed tertiary nerve network of the myenteric plexus and the circular smooth muscle layer. NOS-immunoreactive fibres directed to the circular smooth muscle layer originated from a few NOS-containing perikarya located in the outer submucous plexus. In the colon, caecum and rectum, labelled nerve cells and fibres were numerous in the myenteric plexus; they were also found in the outer submucous plexus. The circular muscle layer had a much denser NOS-immunoreactive innervation than the longitudinally oriented taenia. The marked morphological differences observed between nitrergic neurons within the developing human gastrointestinal tract, together with the typical innervation pattern in the ganglionic and aganglionic nerve networks, support the existence of distinct subpopulations of NOS-containing enterice neurons acting as interneurons or (inhibitory) motor neurons.

Amino Acid Oxidoreductases↗

PubMed2002

Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is regarded as a functional bowel disorder. Few studies have looked for histopathologic changes in the gut and only then in biopsy specimens from intestinal mucosa. Because bowel function is governed mainly by nerve plexuses in the bowel wall, we have investigated full-thickness bowel biopsy specimens in patients with severe IBS. METHODS: We used a laparoscopy-assisted technique to obtain full-thickness biopsy specimens from the proximal jejunum. Tissue specimens were investigated with light microscopy using routine stainings and immunohistochemical techniques. Horizontal sectioning was done to visualize large areas of the myenteric plexus. Fifteen autopsy specimens were used as controls regarding the myenteric plexus. Colorectal adenoma controls with terminal ileum biopsy specimens and full-thickness jejunal biopsy specimens from patients with degenerative enteric neuropathy were used as control groups for intraepithelial lymphocyte counts. RESULTS: Ten patients (2 males, 8 females) were studied. In 9 patients, we found low-grade infiltration of lymphocytes in the myenteric plexus. Lymphocytes had peri- and intraganglionic location. The mean number of lymphocytes per ganglion ranged from 1.9 to 7.1 per patient, with an overall mean of 3.4. No intraganglionic lymphocytes were found in the control group and only a few periganglionic lymphocytes (mean, 0.2). Four patients had concomitant intraepithelial lymphocytosis. Neuron degeneration was evident in 6 of 9 patients with and 1 patient without ganglionic lymphocyte infiltration. CONCLUSIONS: Our findings indicate that inflammation and neuronal degeneration in the myenteric plexus are involved in the pathogenesis of IBS.

Adult↗

PubMed2003

Distribution and chemical coding of cocaine- and amphetamine-regulated transcript peptide (CART)-immunoreactive neurons in the guinea pig bowel.

Cocaine- and amphetamine-regulated transcript-immunoreactive (CART-IR) neurons and nerve fibers were abundant in the submucosal and myenteric plexuses of the guinea pig duodenum, ileum, cecum, proximal and distal colon. CART immunoreactivity was also observed in cell bodies and nerve fibers in the extrahepatic biliary tract. In the myenteric plexus, similar proportions (~20-25%) of neurons were CART-IR in all regions, with the exception of the cecum, where only 13% were CART-IR. In the submucosal plexus, CART-IR was detected in 35-50% of the neurons along the bowel with the exception of the proximal colon (~10%). Multiple label immunohistochemistry in the myenteric plexus of the ileum demonstrated that CART-IR neurons were also immunoreactive for choline acetyltransferase (83%), tachykinins (77%), calbindin (50%), nitric oxide synthase (20%), and/or vasoactive intestinal peptide (23%). In triple label studies, we found that ~8% of the CART-IR neurons were also immunoreactive for both choline acetyltransferase and nitric oxide synthase. CART immunoreactivity was not colocalized with calretinin, somatostatin, or serotonin. These results, combined with previous studies of chemical coding and projection patterns in the guinea pig ileum, indicate that at least four different classes of gut neurons in the myenteric plexus express CART peptide, including excitatory and inhibitory motor neurons projecting to the circular muscle, intrinsic primary afferent neurons, and a subset of descending interneurons. Because all CART-IR neurons in the submucosal plexus were also vasoactive intestinal peptide-IR, they are likely to include secretomotor/vasodilator neurons.

Animals↗

PubMed1995

Involvement of eicosanoids and macrophage-like cells in cytokine-mediated changes in rat myenteric nerves.

BACKGROUND & AIMS: Proinflammatory cytokines alter function in enteric nerves, but little is known about underlying mechanisms. This study was designed to investigate the roles of prostanoids and of macrophage-like cells in cytokine-induced suppression of [3H]norepinephrine release from rat myenteric plexus. METHODS: The release of 3H from jejunal longitudinal muscle-myenteric plexus preparations that had been loaded with [3H]norepinephrine was measured. Measurements of 3H release as well as concentrations of prostaglandin E2 and leukotriene were made in preparations exposed to interleukin 1 beta plus interleukin 6 and in the presence or absence of piroxicam, 5-lipoxygenase inhibitor MK886, cycloheximide, or cyclosporin A. An ultrastructural analysis was also performed to investigate the presence of macrophage-like cells in the myenteric plexus. RESULTS: Interleukin 1 beta plus interleukin 6 suppressed 3H release and caused an increase in tissue prostaglandin E2 but not leukotriene E4. Piroxicam and cycloheximide but not MK886 attenuated the cytokine-induced increase in prostaglandin E2 and the suppression of [3H]norepinephrine release. Ultrastructural analysis showed macrophage-like cells in the plexus, and the cytokine effects were inhibited by cyclosporin A. CONCLUSIONS: Prostanoids but not leukotrienes mediate the cytokine-induced suppression of norepinephrine release, and the results of this study suggest that macrophage-like cells are also involved.

Analysis of Variance↗

PubMed1998

Ultrastructural characterization of interstitial cells of Cajal in the rat small intestine using control and Ws/Ws mutant rats.

Interstitial cells in the myenteric plexus and the deep muscular plexus of the small intestine of the c-kit mutant rats (Ws/Ws) and their normal siblings (+/+) were studied. c-Kit immunoreactivity was detected in two regions corresponding to the myenteric plexus and the deep muscular plexus in the jejunum of +/+ rats, while no immunoreactivity was detected in Ws/Ws rats. Using electron microscopy, two types of gap junction-forming interstitial cells were found in association with the myenteric plexus in +/+ rats: one type characterized by a typical fibroblastic ultrastructure, and the other characterized by numerous mitochondria and less electron-dense cytoplasm. Since the latter were greatly reduced in Ws/Ws rats, it was suggested that these cells correspond to c-kit-expressing cells, i.e. interstitial cells of Cajal in the myenteric plexus region. In contrast, two types of interstitial cells in the region of the deep muscular plexus were observed with no difference between +/+ and Ws/Ws rats. Probable interstitial cells of Cajal in this region were characterized by a basal lamina and numerous caveolae as well as large gap junctions that interconnect with each other and with the smooth muscle cells. We concluded that interstitial cells of Cajal in the rat intestine are heterogeneous in ultrastructure, c-kit dependency in the cell maturation, and functional role.

Animals↗

PubMed1991

Morphology and projections of myenteric neurons to colonic fiber bundles of the cat.

Regulation of colon function depends on the location of nerve cell bodies and the distribution of intrinsic nerve fibers in the myenteric plexus. The morphology and projections of myenteric neurons through colonic fiber bundles in cat colon were determined using in vivo retrograde transport of HRP and Fast blue. Myenteric neurons were found to project from at least 5 to 59 mm orad (mean: 42 mm) or aborad (mean: 54 mm) through colonic fiber bundles. Approximately 73% of labelled cells were in ganglia within 2.8 mm of colonic fiber bundles in the axis of circular muscle fibers; none was beyond 7.7 mm. There were 2 soma morphologies. One type (Dogiel type I) had a mean soma diameter of 40.5 microns and had a rough somal surface. There were few if any short, broad dendrites, but its one long process extended to a branch point of an adjacent colonic fiber bundle. The other type (Dogiel type III) had a mean soma diameter of 26.4 microns, had a smooth somal surface and had few if any fine dendrites. It also projected a single long axon to colonic fiber bundles. There were twice as many Dogiel type III neurons. We conclude that myenteric neurons in the cat colon project both orad and aborad over relatively long distances through colonic fiber bundles where they form another intrinsic neuronal connection for the myenteric plexus.

Afferent Pathways↗

PubMed1985

Distribution of galanin-like immunoreactivity in the gastro-intestinal tract of several mammalian species.

The distribution of galanin-immunoreactive (GAL-IR) neurons was mapped in detail in the gastro-intestinal tract of the rat, mouse, guinea-pig and pig by use of the indirect immunofluorescence technique. GAL-IR cell bodies were found in both the submucous and the myenteric plexus, with considerably higher numbers in the former ganglia. The largest number of GAL-IR perikarya was seen in the duodenal submucous plexus of the pig. With some (single) exceptions, GAL-IR cell somata were not observed in the myenteric plexus of the pig and guinea-pig, and in the submucous plexus of the esophagus and the stomach of the guinea-pig. GAL-IR fibers occurred in most parts of the gastro-intestinal tract. In the lamina propria a few non-varicose, weakly fluorescent fibers were noted in the mouse and rat, whereas in the pig and guinea-pig were large numbers of GAL-IR fibers with a varicose appearance was observed. These fibers were in all species most numerous in the distal portion of the intestinal tract. In the submucosa GAL-IR fibers were detected in all four species, and in the pig and guinea-pig some fibers surrounded blood vessels. A large number of GAL-IR fibers was generally seen in the circular smooth muscle layer, except in the guinea-pig, which only seemed to contain a few fibers. In the longitudinal muscle layer only single fibers could be detected. However, the gastric fundus region of the pig contained a moderate number of fibers in the longitudinally and obliquely oriented layers. In general, in the rat, mouse and pig, the submucous and myenteric plexus contained moderate or large numbers of GAL-IR fibers. In the guinea-pig, no or only single fibers were observed in the plexus of the upper gastro-intestinal tract and the rectum, while moderate numbers were seen in the ileum and colon. Thin adjacent sections stained for vasoactive intestinal polypeptide (VIP) and GAL revealed the coexistence of these two peptides in cell bodies of the myenteric plexus in the pig duodenum and guinea-pig colon. In these two species the GAL- and VIP-nerve fiber networks also exhibited marked similarities. However, in the rat and mouse VIP- and GAL-distribution patterns were in general different. The present findings indicate the presence of yet another neuropeptide or peptide family in the gastro-intestinal tract of several rodents and the pig.

Animals↗

PubMedDate not supplied

Distribution of NADPH diaphorase in intramural plexuses of cat and opossum esophagus.

Nonadrenergic noncholinergic (NANC) nerves, releasing nitric oxide (NO), regulate peristalsis in esophageal smooth muscle. The NADPH diaphorase reaction identifies nitric oxide synthase (NOS). NO-synthesizing (NANC) nerves should be more abundant in esophageal smooth muscle than in striated muscle. We used NADPH diaphorase histochemistry in whole-mounts of the esophagus of cat (predominantly striated muscle) and opossum (predominantly smooth muscle) to compare striated and smooth muscle regions. In the opossum myenteric plexus, 90% of nerve cells were stained, with two populations, dark-staining and light-staining cells. Dark cells constituted 35-51% of stained cells with no difference between striated muscle and smooth muscle regions. In the cat myenteric plexus, 50% of cells were unstained in the striated muscle segment, but only 10% in the smooth muscle segment. Stained cells constituted two populations, dark cells and light cells, dark cells making up 48-60% of stained cells in both striated and smooth muscle segments, with no difference between segments. Both dark cells and light cells lay in clusters in opossum, but not in cat. Dark cells showed no selectivity for large or small ganglia of myenteric plexus in either region in opossum. Many more NADPH diaphorase positive nerve fibers lay in the circular smooth muscle layer than in the other layers. They were not found in striated muscle. Interstitial cells of Cajal in the circular layer of smooth muscle were also positive. In the submucosal plexus of opossum, all cells were stained, 10% being dark cells in both striated and smooth muscle segments. The cat has almost no nerve cells in the submucosal plexus. The similarity of the myenteric plexus in striated muscle and smooth muscle regions of the esophagus suggests that NADPH diaphorase positive nerves have other functions besides regulation of smooth muscle. Also, a positive reaction may not dictate that NO is the sole transmitter released.

Animals↗

PubMed1991

An attempt to localize the site of action of different agents within cholinergic motor neurones of the myenteric plexus-longitudinal muscle preparation of the guinea pig ileum by the triple bath method.

The site of action of cholinergic, adrenergic, peptidergic and opioid agents was studied in myenteric plexus-longitudinal muscle strips from the guinea pig ileum. A preparation in a special triple bath was drawn through two rubber membranes, dividing the strip into three segments. Neurogenic stimulation of the oral segment, set up nerve action potentials also in the neurones projecting axons up to the aboral segment. These axons, turning into varicose nerve terminals, conducted action potentials aborally across the middle segment, that was up to 10 mm wide. Finally, the nerve terminals, extending into the aboral segment, might be also invaded triggering twitches. Agents were added, either to the oral segment, to affect the genesis and spread of action potentials in the proximal parts of cholinergic neurones (cell bodies, axon hillocks, initial segments and axon preterminals) or they were added to the middle segment to affect propagation of action potentials in varicose nerve terminals. As a result, the amplitude of aboral twitches reflected their effects at each site, quantitatively. Noradrenaline and ethylketocyclazocine were more effective at the site of varicose nerve terminals, whereas substance P, acetylcholine and oxotremorine were more effective at the proximal parts; pilocarpine and nicotine were effective at both sites. Changes in membrane polarization might be the final common effect in the mechanism of action of all the stimulatory agents used.

Action Potentials↗

PubMed2006

Possible involvement of muscularis resident macrophages in impairment of interstitial cells of Cajal and myenteric nerve systems in rat models of TNBS-induced colitis.

Resident macrophages are distributed in the network of interstitial cells of Cajal (ICC) and the myenteric nerve within the myenteric plexus. We evaluated changes in chemoattractant protein mRNA expression in macrophages and neutrophils, the ICC, nerve and macrophages in the myenteric plexus of model rats with TNBS-induced colitis. Chemoattractant proteins, MCP-1, GRO, MIP-2 and CINC-2alpha were upregulated in the colonic muscle layer after inflammation. Leukocyte infiltration and MPO activity were increased in the muscle layer. Electron microscopy indicated an irregular contour of the myenteric ganglia into which numerous macrophages had penetrated. Macrophages were also distributed near the ICC in the inflamed myenteric plexus. Immunohistochemistry showed that the ICC network and myenteric nerve system had disappeared from the inflamed region, whereas the number of resident macrophages was increased. TTX-insensitive, possibly ICC-mediated, rhythmic contractions of circular smooth muscle strips and enteric neuron-mediated TTX-sensitive peristalsis in the whole proximal colon tissue were significantly inhibited in the inflamed colon, indicating that the ICC-myenteric nerve system was dysfunctional in the inflamed muscle layer. Their accumulation around the myenteric nerve plexus and the ICC network suggests that macrophages play an important role in inducing intestinal dysmotility in gut inflammation.

Animals↗

PubMed2002

Na+, K+ ATPase alpha-subunit isoform distribution and abundance in guinea-pig longitudinal muscle/myenteric plexus after exposure to morphine.

Previous work in the myenteric plexus has shown that the resting membrane potential of morphine-tolerant guinea-pig myenteric S neurons is significantly depolarized relative to placebo-implanted controls, and that this depolarization is associated with reduced electrogenic Na+, K+ pumping. Identification of the subunits of the sodium pump which are in the myenteric plexus was undertaken in order to facilitate direct qualitative and quantitative measurements of the abundance of sodium pump isoforms after morphine exposure, thereby confirming and extending the electrophysiological data to the molecular level. Seven days prior to the experiments, tolerance was induced by subcutaneous implantation of morphine pellets (one pellet, 75 mg/100 g body weight) while control guinea pigs received placebo pellets. Using immunohistochemistry and confocal microscopy, the distribution of the alpha subunit isoforms of the Na+/K+ -ATPase in placebo and morphine-tolerant guinea-pig ileum was determined. Only the alpha1 and alpha3 subunit isoforms were in sufficient abundance to be observed. The alpha1 subunit isoform was most highly concentrated in the mucosa and in neurons. In contrast, the alpha3 subunit isoform was uniquely localized to neurons. Western and slot blot analyses of longitudinal muscle/myenteric plexus homogenates identified a significant reduction of the alpha3 but not the alpha1 subunit isoform in tolerant preparations. It is concluded that the reduced electrogenic pumping in the S neurons after morphine exposure is associated with a reduction in the alpha3 subunit isoform.

Animals↗

PubMed1989

1,3-Di(2-tolyl)guanidine blocks nicotinic response in guinea pig myenteric neurons.

Ditolylguanidine (DTG) is a ligand which binds with high affinity to neuronal sigma receptors. Activation of sigma receptors inhibits the release of acetylcholine (ACh) from guinea pig ileum myenteric plexus preparations. A study was therefore undertaken to investigate the action of sigma receptor ligands on single neurons. Nicotinic responses to locally applied ACh onto single neurons of the guinea pig ileum myenteric plexus were studied using intracellular recording techniques. DTG and (+)-SKF10047 (N-allylnormetazocine) produced a concentration-dependent suppression of the depolarization of enteric neurons evoked by ionophoresis of ACh. The EC50 values for DTG and (+)-SKF10047 were 4.7 and 3.8 microM, respectively, and were similar to that for hexamethonium (3.2 microM). The inhibition of the ACh-depolarization was not mediated at sigma receptors because (-)SKF10047 and Bridge-DPG (2-imino-1,3H-dibenzo[d,f]-[1,3]-diazepine), which are inactive at sigma receptors, were as potent as DTG and (+)-SKF10047. DTG and hexamethonium (each at 1 microM) were more effective blockers of ACh-induced inward currents at a holding potential of -100 mV than at -40 mV. This voltage dependence is consistent with a channel blocking mechanism. DTG (10 microM) did not affect the depolarization (mediated by 5-HT3 receptors) induced by pressure application of 5-HT onto single neurons. DTG and Bridge-DPG inhibited contractures of the longitudinal muscle-myenteric plexus preparation elicited by dimethylphenylpiperazinium noncompetitively (EC50 values were 8.0 and 12.3 microM, respectively) whereas DTG but not Bridge-DPG inhibited 5-HT-induced contractions of the longitudinal muscle-myenteric plexus noncompetitively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2002

The pathogenesis of pseudoachalasia: a clinicopathologic study of 13 cases of a rare entity.

Pseudoachalasia is an esophageal motor disorder usually associated with malignancy that has clinical, radiographic, and manometric findings that are often indistinguishable from primary achalasia. There are few reports examining the histologic features of the associated neoplasms and their relationship with the esophageal myenteric plexus. We studied the clinical and pathologic features of 13 cases of pseudoachalasia seen at our institution between 1979 and 1999. Detailed clinical and radiographic data were obtained from medical records. In all cases available histologic material was reviewed to confirm the presence and type of associated neoplasm. When possible, the relationship of the neoplasm to the esophageal myenteric plexus was examined. In selected cases immunohistochemical stains were performed to further evaluate this relationship. All patients had clinical, radiographic, and manometric features similar to primary achalasia. The cohort included seven men and six women, age range 24-79 years (median 61 years). Associated neoplasms included esophageal adenocarcinoma arising in Barrett's esophagus (n = 1), adenocarcinoma of the esophagogastric junction (n = 7), metastatic renal cell carcinoma to the esophagogastric junction (n = 1), breast adenocarcinoma (n = 1), pulmonary small cell carcinoma (n = 1), pleural malignant mesothelioma (n = 1), and mediastinal fibrosis (n = 1). The mechanism of pseudoachalasia was consistent with neoplastic infiltration of the esophageal myenteric plexus in 11 cases. Neoplastic cells surrounded myenteric ganglion cells, which appeared normal in number and morphology. In the patient with pulmonary small cell carcinoma, there was no evidence of neoplastic infiltration of the esophagogastric junction, and anti-ANNA-1 antibody was detected, suggesting a paraneoplastic syndrome. Tissue obtained at the time of esophagomyotomy revealed lymphocytic myenteric inflammation and marked depletion of ganglion cells identical to that seen in primary achalasia. The mechanism pseudoachalasia in the patient with breast adenocarcinoma is uncertain, as there was no evidence of direct involvement of the esophagogastric junction. In summary, we describe 13 cases of pseudoachalasia resulting in a clinical syndrome indistinguishable from primary achalasia. The most common mechanism is direct involvement of the esophageal myenteric plexus by neoplastic cells. Rarely, a distant neoplasm may cause this syndrome as a paraneoplastic process.

Adenocarcinoma↗

PubMed1984

Origins and three-dimensional distribution of substance P-containing structures on the rat stomach using whole-mount tissue.

The origin and three-dimensional distribution of substance P-immunoreactive structures in the rat stomach were investigated by means of the indirect immunofluorescence method using whole-mount tissue. The present study demonstrated that the myenteric plexus contained a very high concentration of substance P-immunoreactive fibers. It also contained cells that were moderately concentrated in the greater curvature, with those closer to the lesser curvature decreasing in number. In addition, a number of fibers ran parallel to the muscles in the circular and longitudinal muscle layers; these were distributed evenly throughout the entire stomach. We further found that most of the fibers located in the myenteric plexus originated from the greater splanchnic nerve from T5 to L2, but that some originated from intrinsic substance P-immunoreactive cells in the myenteric plexus. The fibers in the circular and longitudinal muscle layers originated from the cells in the myenteric plexus.

Animals↗

PubMed1983

Gamma-aminobutyrate as an autonomic neurotransmitter: release and uptake of [3H]gamma-aminobutyrate in guinea pig large intestine and cultured enteric neurons using physiological methods and electron microscopic autoradiography.

To provide further evidence that some enteric neurons use gamma-aminobutyrate (GABA) as a neurotransmitter, we have demonstrated a depolarization-induced release of [3H]GABA from isolated myenteric ganglia in culture, and from segments of large intestine containing the myenteric plexus. In addition, light and electron microscopic autoradiography has been employed to visualize the putative GABAergic neurons and their projections, both in cultured ganglia and in sections from the gut wall. Explant cultures of the guinea-pig myenteric plexus, containing only neurons and glia intrinsic to the gut, were incubated with 0.14 microM [3H]GABA, washed and then repeatedly depolarized by 62 mM K+. The depolarizations always evoked release of [3H]GABA. The evoked release was reversibly blocked by 5 mM Co2+, suggesting a dependence on Ca2+ influx, a characteristic of neuronal transmitter release. Strips of the guinea-pig taenia coli, containing the myenteric plexus, were incubated with 0.14 or 0.7 microM [3H]GABA, washed and subjected to electrical field stimulation. This caused release of [3H]GABA, which could be evoked successively on repeated stimulation. The release was of neuronal origin and Ca2+ dependent, since it was abolished by 3 microM tetrodotoxin and reversibly blocked by 10 mM Co2+. By combined electrophoresis and chromatography the released tritium was identified as being attached to GABA. Autoradiography, following incubation with low concentrations of [3H]GABA, was used to identify specifically putative GABAergic neurons. Light microscopic autoradiography of cultured ganglia, and electron microscopic autoradiography of sections from the taenia coli including the myenteric plexus, were in good agreement, showing a selective and heavy labelling over a sub-population of neurons, and light labelling over glial cells. The majority of neurons and the non-neural cells were unlabelled. The electron microscopic autoradiographs also showed heavy labelling over some, but not all, axons in the fine axon bundles that innervate the longitudinal muscle of the taenia. These results strongly support our previous suggestion that a population of myenteric neurons are GABAergic, although more work is needed before this is fully established. Our data also suggest that some of the putative GABAergic neurons project out to the gut musculature, where their axons, together with axons from other neurons, run in bundles to form the intramuscular nerves. We therefore propose that one of the roles of these neurons in the gut is the presynaptic modulation of transmitter released from neighbouring axons in these nerves.

Animals↗

PubMed1995

The interaction of RS 25259-197, a potent and selective antagonist, with 5-HT3 receptors, in vitro.

1. A series of isoquinolines have been identified as 5-HT3 receptor antagonists. One of these, RS 25259-197 [(3aS)-2-[(S)-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro- 1- oxo-1H-benzo[de]isoquinoline-hydrochloride], has two chiral centres. The remaining three enantiomers are denoted as RS 25259-198 (R,R), RS 25233-197 (S,R) and RS 25233-198 (R,S). 2. At 5-HT3 receptors mediating contraction of guinea-pig isolated ileum, RS 25259-197 antagonized contractile responses to 5-HT in an unsurmountable fashion and the apparent affinity (pKB), estimated at 10 nM, was 8.8 +/- 0.2. In this tissue, the -log KB values for the other three enantiomers were 6.7 +/- 0.3 (R,R), 6.7 +/- 0.1 (S,R) and 7.4 +/- 0.1 (R,S), respectively. The apparent affinities of RS 25259-197 and RS 25259-198, RS 25233-197 and RS 25233-198 at 5-HT3 receptors in membranes from NG-108-15 cells were evaluated by a [3H]-quipazine binding assay. The -log Ki values were 10.5 +/- 0.2, 8.4 +/- 0.1, 8.6 +/- 0.1 and 9.5 +/- 0.1, respectively, with Hill coefficients not significantly different from unity. Thus, at these 5-HT3 receptors, the rank order of apparent affinities was (S,S) > (R,S) > (S,R) = (R,R). 3. RS 25259-197 displaced the binding of the selective 5-HT3 receptor ligand, [3H]-RS 42358-197, in membranes from NG-108-15 cells, rat cerebral cortex, rabbit ileal myenteric plexus and guinea-pig ileal myenteric plexus, with affinity (pKi) values of 10.1 +/- 0.1, 10.2 +/- 0.1, 10.1 +/- 0.1 and 8.3 +/- 0.2, respectively. In contrast, it exhibited low affinity (pKi <6.0) at 28 other receptors in binding assays, including adrenoceptors (alpha1A, alpha 1B, alpha2A, alpha 2B ,beta1, beta2), muscarinic (M1-M4), dopamine (D1, D2), opioid and other 5-HT(5-HTlA, 5-HTlD, 5-HT2C, 5-HT4) receptors.4. RS 25259-197 was tritium labelled (specific activity: 70 Ci mmol-1) and evaluated in pharmacological studies. Saturation studies with [3H]-RS 25259-197 in membranes from NG-108-15 and cloned homomeric a subunits of the 5-HT3 receptor from N1E-1 15 cells expressed in human kidney 293E1 cells,revealed an equilibrium dissociation constant (Kd) of 0.05 +/- 0.02 and 0.07 +/- 0.01 nM, and Bmax of610 +/- 60 and 1068 +/- 88 fmol mg-1, respectively. Competition studies in NG-108-15 cells indicated a pharmacological specificity entirely consistent with labelling a 5-HT3 receptor, i.e. RS 25259-197> granisetron> (S)-zacopride> tropisetron> (R)-zacopride> ondansetron> MDL 72222.5. In contrast to the majority of radioligands available to label 5-HT3 receptors, [3H]-RS 25259-197 labelled a high affinity site in hippocampus from human post-mortem tissue with an equilibrium dissociation constant (Kd) of 0.15 +/- 0.07 nM and density (BmaX) of 6.8 +/- 2.4 fmol mg-1 protein. Competition studies in this tissue indicated a pharmacological specificity consistent with labelling of a 5-HT3receptor.6. Quantitative autoradiographic studies in rat brain indicated a differential distribution of 5-HT3receptor sites by [3H]-RS 25259-197. High densities of sites were seen in nuclear tractus solitaris and area postrema, a medium density in spinal trigeminal tract, ventral dentate gyrus and basal medial amygdala,and a low density of sites in hippocampal CAl, parietal cortex, medium raphe and cerebellum.7 In conclusion, the functional, binding and distribution studies undertaken with the radiolabelled and non-radiolabelled RS 25259-197 (S,S enantiomer) established the profile of a highly potent and selective5-HT3 receptor antagonist.

Animals↗