Evidence for a glutamatergic neural pathway in the myenteric plexus

Wiley, John W.; Lu, Yuanxu; Owyang, Chung

doi:10.1152/ajpgi.1991.261.4.g693

Cited by 39 publications

(58 citation statements)

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“…In addition, glutamate depolarizes enteric neurons and mediates fast synaptic transmission in the ENS (Liu et al, 1997). Pharmacological studies have also been consistent with the idea that neurogenic motile (Shannon and Sawyer, 1989;Wiley et al, 1991) or secretory (Rhoads et al, 1995) responses of the gut involve enteric glutamatergic receptors.The abundance of subsets of glutamate receptors that increase [Ca 2ϩ ] i (MacDermott et al, 1986;Hollmann et al, 1991) in the ENS may render enteric neurons vulnerable to glutamatemediated neurotoxicity. The neurotoxic effects of glutamate in the ENS have not been examined; therefore, we determined whether excitotoxicity occurs in guinea pig enteric neurons.…”

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confidence: 52%

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Excitotoxicity in the Enteric Nervous System

1997

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Glutamate, the major excitatory neurotransmitter in the CNS, is also an excitatory neurotransmitter in the enteric nervous system (ENS). We tested the hypothesis that excessive exposure to glutamate, or related agonists, produces neurotoxicity in enteric neurons. Prolonged stimulation of enteric ganglia by glutamate caused necrosis and apoptosis in enteric neurons. Acute and delayed cell deaths were observed. Glutamate neurotoxicity was mimicked by NMDA and blocked by the NMDA antagonist D-2-amino-5-phosphonopentanoate. Excitotoxicity was more pronounced in cultured enteric ganglia than in intact preparations of bowel, presumably because of a reduction in glutamate uptake. Glutamate-immunoreactive neurons were found in cultured myenteric ganglia, and a subset of enteric neurons expressed NMDA (NR1, NR2A/B), AMPA (GluR1, GluR2/3), and kainate (GluR5/6/7) receptor subunits. Glutamate receptors were clustered on enteric neurites. Stimulation of cultured enteric neurons by kainic acid led to the swelling of somas and the growth of varicosities ("blebs") on neurites. Blebs formed close to neurite intersections and were enriched in mitochondria, as revealed by rhodamine 123 staining. Kainic acid also produced a loss of mitochondrial membrane potential in cultured enteric neurons at sites where blebs tended to form. These observations demonstrate, for the first time, excitotoxicity in the ENS and suggest that overactivation of enteric glutamate receptors may contribute to the intestinal damage produced by anoxia, ischemia, and excitotoxins present in food. Key words: necrosis; apoptosis; NMDA; kainic acid; glutamate transporters; bleb formation; rhodamine 123Excessive exposure to glutamate causes cell death ("excitotoxicity") in C NS neurons (Choi, 1988(Choi, , 1995. E xcitotoxicity consists of necrosis and apoptosis and is thought to occur via a breakdown in ionic homeostasis mediated by NMDA and non-NMDA glutamate receptor subtypes. Neurons can be protected from excitotoxicity by C a 2ϩ buffers (T ymianski et al., 1993); therefore, increases in [C a 2ϩ ] i are involved in causing excitotoxic cell death (Choi, 1988(Choi, , 1992. Consistent with this idea, both NMDA and kainic acid increase [C a 2ϩ ] i in central neurons (MacDermott et al., 1986;Brorson et al., 1994). Moreover, excessive exposure to either glutamate receptor agonist produces neuronal cell loss . Increases in [C a 2ϩ ] i produced by these excitotoxins occur at sites that are rich in mitochondria and produce a loss of mitochondrial membrane potential (Ankarcrona et al., 1995;Bindokas and Miller, 1995). Mitochondrial f unction seems to determine the mode of neuronal death in excitotoxicity. Early necrosis develops in neurons that lose mitochondrial membrane potential. Delayed apoptosis develops in neurons that recover mitochondrial potential and energy levels.Substantial evidence suggests that glutamate is an excitatory neurotransmitter in the enteric nervous system (ENS). The bowel contains glutamate-immunoreactive neurons, enteric neurons express ...

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confidence: 52%

supporting

confidence: 52%

Excitotoxicity in the Enteric Nervous System

1997

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“…Furthermore, electrical activity recorded from the distal ends of cut vagal afferents is modulated by NMDA receptors (42), suggesting that receptors in peripheral vagal afferent membranes may participate in relaying sensory information to the brain. Immunoreactivity for glutamate and vesicular glutamate transporter (VGLUT) has been reported in neurons of enteric plexus of the guinea pig and rat small intestines (45,51). Likewise, immunoreactivity to glutamate has been reported in the intrinsic and extrinsic innervations of the human digestive tract (15), and there is compelling evidence that at least some gastrointestinal vagal afferent terminals are immunoreactive for VGLUTs (32).…”

Section: Discussionmentioning

confidence: 99%

Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors

Wright

Campos

Herzog

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of D-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (D-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, DCPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.vagus; satiation; gut-brain peptides SATIATION IS THE PROCESS by which food entering the gastrointestinal tract gradually reduces food intake, eventually resulting in termination of a meal. Previous reports from our group and others indicate that systemic administration of antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAr antagonists) delays satiation and increases meal size (see, for example, Refs. 8, 9, and 25). Additionally, we demonstrated that injecting NMDAr antagonists directly into the nucleus of the solitary tract (NTS), where vagal afferents from the gastrointestinal tract synapse, increases meal size (19,23,46) and that lesions of the NTS abolish this effect (47). These observations suggest that NMDA receptors, perhaps in the NTS, participate in vagally mediated control of food intake.The hypothesis that NMDA receptors participate in the process of satiation is supported by our prior reports that peripherally administered NMDA receptor antagonists attenuate reduction of food intake induced by CCK (11, 19), a gut peptide known to reduce food intake by activating abdominal vagal a...

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“…Although the activation of nAChRs is the predominant mechanism of excitatory neurotransmission in the ENS, pioneering work initiated by Burnstock in the 1960s (Burnstock et al, 1966;Ambache and Freeman, 1968;Furness et al, 1989;Wiley et al, 1991;Galligan, 1999a, 1999b) demonstrated that autonomic nerves can release many noncholinergic, nonadrenergic neurotransmitters and that multiple mechanisms can contribute to fast synaptic transmission in enteric neurons. Neurons in the ENS can be distinguished on the basis of their electrophysiologic properties into S and AH neurons (Hirst and McKirdy, 1974).…”

Section: Nachrs In the Control Of Gut Functionmentioning

confidence: 99%

Nicotinic mechanisms in the autonomic control of organ systems

Biasi

2002

J. Neurobiol.

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Evidence for a glutamatergic neural pathway in the myenteric plexus

Cited by 39 publications

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Excitotoxicity in the Enteric Nervous System

Excitotoxicity in the Enteric Nervous System

Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors

Nicotinic mechanisms in the autonomic control of organ systems

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