Metabotropic glutamate receptors inhibit mechanosensitivity in vagal sensory neurons

Page, Amanda J.; Young, Richard L.; Martin, C. M.; Umaerus, M.; O’Donnell, Tracey A.; Cooper, Nicole J.; Coldwell, Jonathan R.; Hulander, Malin; Mattsson, Jan P.; Lehmann, Anders; Blackshaw, L. Ashley

doi:10.1053/j.gastro.2004.11.062

Cited by 80 publications

(88 citation statements)

References 31 publications

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“…This discrepancy between studies may be a regional difference, because all afferents recorded in the present study were located in the esophagus or the LES and were therefore a totally different anatomical population than the gastric afferents previously reported (20). However, it should be noted that the esophageal tension receptors on which we observed effects of DAMGO are otherwise indistinguishable in their pharmacology from gastric tension receptors in ferret (21,25,26), suggesting a species variation.…”

Section: Discussioncontrasting

confidence: 80%

Opioid modulation of ferret vagal afferent mechanosensitivity

Page¹,

O’Donnell²,

Blackshaw³

2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Page AJ, O'Donnell TA, Blackshaw LA. Opioid modulation of ferret vagal afferent mechanosensitivity. Am J Physiol Gastrointest Liver Physiol 294: G963-G970, 2008. First published February 7, 2008 doi:10.1152/ajpgi.00562.2007.-Despite universal use of opioids in the clinic to inhibit pain, there is relatively little known of their peripheral actions on sensory nerve endings, where in fact they may be better targeted with more widespread applications. Here we show differential effects of -, -, and ␦-opioids on mechanosensitive ferret esophageal vagal afferent endings investigated in vitro. The effects of selec- -80), respectively, on mechanosensory stimulus-response functions were quantified. DAMGO (10 Ϫ7 to 10 Ϫ5 M) reduced the responses of tension receptors to circumferential tension (1-5 g) by up to 50%, and the responses of mucosal receptors to mucosal stroking (10 -1,000 mg von Frey hair) by Ͼ50%. DAMGO effects were reversed by naloxone (10 Ϫ5 M). Tension/mucosal (TM) receptor responses to tension and stroking were unaffected by DAMGO. ICI 199441 (10 Ϫ6 to 10 Ϫ5 M) potently inhibited all responses except TM receptor responses to tension, and SNC-80 (10 Ϫ5 to 10 Ϫ3 M) had no effect other than a minor inhibition of mucosal receptor responses to intense stimuli at 10 Ϫ3 M. We conclude that -and -opioids have potent and selective peripheral effects on esophageal vagal afferents that may have applications in treatment of disorders of visceral sensation. vagal afferents; neuromodulation; esophagus OPIOID RECEPTORS WERE IDENTIFIED more than 30 years ago as the primary targets with which morphine and its derivatives interact to exert their analgesic and other effects. The receptors, along with their endogenous ligands, enkephalins, endorphins, and other opioid peptides, are widely distributed in the central and peripheral nervous system and play an important role in modulating endocrine, immune, cardiovascular, and gastrointestinal functions. Three major types of opioid receptors, , ␦, and , have been defined pharmacologically. Both spinal and vagal sensory neurons express different numbers of -, ␦-, and -opioid receptors that are transported into the peripheral axons (1,13,15,17,31). The -opioid receptor (KOR) agonist fedotozine decreases sensitivity of rat visceral afferents to gastric and colonic distension (7). Despite robust effects of KOR ligands, -and ␦-opioid receptor agonists have not been found to affect mechanosensitivity in these models (20, 34), indicating selectivity of expression within rodent distensionsensitive afferents. The effect of opioid agonists in other species and on different classes of visceral afferents is unknown: for instance mucosal mechanoreceptors, which only respond to mucosal stroking (22, 23). Such effects may have an important bearing on interpretation of clinical findings, such as the inhibitory effect of the -opioid receptor (MOR) agonist morphine on triggering of transient lower esophageal sphincter (LES) relaxation by gastric distension in humans (27) and the effect of opioids...

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Section: Discussioncontrasting

confidence: 80%

Opioid modulation of ferret vagal afferent mechanosensitivity

Page¹,

O’Donnell²,

Blackshaw³

2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Note that we examined only ionotropic receptors; the presence of GABA and glutamate metabotropic receptors in vagal brain stem circuits (17,21,35,38,47,48,60) adds another potentially larger level of complexity. Indeed, in the present study we did not examine the contribution of metabotropic receptors to the basal firing rate of DMV neurons and thus we cannot exclude their activation; however, we did not observe any significant effect on the DMV membrane induced by the GABA B antagonist saclofen (17) or Kynurenic acid was applied first, followed by bicuculline.…”

Section: Discussionmentioning

confidence: 99%

Differential organization of excitatory and inhibitory synapses within the rat dorsal vagal complex

Babic

Browning

Travagli

2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Babic T, Browning KN, Travagli RA. Differential organization of excitatory and inhibitory synapses within the rat dorsal vagal complex. Am J Physiol Gastrointest Liver Physiol 300: G21-G32, 2011. First published October 14, 2010 doi:10.1152/ajpgi.00363.2010.-The dorsal motor nucleus of the vagus (DMV) is pivotal in the regulation of upper gastrointestinal functions, including motility and both gastric and pancreatic secretion. DMV neurons receive robust GABA-and glutamatergic inputs. Microinjection of the GABAA antagonist bicuculline (BIC) into the DMV increases pancreatic secretion and gastric motility, whereas the glutamatergic antagonist kynurenic acid (KYN) is ineffective unless preceded by microinjection of BIC. We used whole cell patch-clamp recordings with the aim of unveiling the brain stem neurocircuitry that uses tonic GABA-and glutamatergic synapses to control the activity of DMV neurons in a brain stem slice preparation. Perfusion with BIC altered the firing frequency of 71% of DMV neurons, increasing firing frequency in 80% of the responsive neurons and decreasing firing frequency in 20%. Addition of KYN to the perfusate either decreased (52%) or increased (25%) the firing frequency of BIC-sensitive neurons. When KYN was applied first, the firing rate was decreased in 43% and increased in 21% of the neurons; further perfusion with BIC had no additional effect in the majority of neurons. Our results indicate that there are several permutations in the arrangements of GABA-and glutamatergic inputs controlling the activity of DMV neurons. Our data support the concept of brain stem neuronal circuitry that may be wired in a finely tuned organ-or function-specific manner that permits precise and discrete modulation of the vagal motor output to the gastrointestinal tract. electrophysiology; vagus; brain stem SENSORY INFORMATION FROM THE gastrointestinal (GI) tract is encoded by chemo-and mechanoreceptors with different modalities, responses, and properties (reviewed in Ref. 11). Regardless of their function(s) or modalities, however, primarily nonnoxious visceral sensory information is transmitted through the afferent vagus into the brain stem via a glutamatergic synapse at the level of the nucleus tractus solitarius (NTS) (2,3,8,54). The NTS comprises various subnuclei that appear to be organized viscerotopically (1, 9, 57), such that the vagal sensory input from each visceral organ is concentrated in a particular subnucleus. The subnucleus centralis, for example, receives inputs almost exclusively from the esophagus.The motor output to the GI tract is provided by the spontaneously firing neurons of the dorsal motor nucleus of the vagus (DMV), which, in contrast to NTS neurons, are organized in neuronal "columns" that project to the viscera through each of the five subdiaphragmatic vagal branches (reviewed in Ref. 57). DMV neurons within each column, however, are not identical but comprise heterogeneous neuronal populations that differ in their neurochemical, morphological, and electrophysiological prope...

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“…57 mGluR expression has been demonstrated on gastric vagal afferents by retrograde tracers in the ferret. 58 The known inhibitory effect of group II and III mGluR and the excitatory effect of group I mGluR were also demonstrated as a decrease and increase in vagal afferent mechanosensitivity. 58 mGluR5 labelling is abundant in gastric vagal afferent neurons but sparse in fibres within NTS vagal subnuclei.…”

Section: Metabotropic Glutamatementioning

confidence: 98%