The nucleus tractus solitarius (NTS) receives visceral information from the gastrointestinal, car... more The nucleus tractus solitarius (NTS) receives visceral information from the gastrointestinal, cardiovascular and respiratory systems via type-A and type-C fibers. NTS nucleus centralis (cNTS) recei...
Endoscopic retrograde cholangiopancreatography (ERCP) is a procedure used to identify biliary duc... more Endoscopic retrograde cholangiopancreatography (ERCP) is a procedure used to identify biliary duct obstruction. 5-10% of patients, however, develop acute pancreatitis (AP). AP is a severe disorder ...
Perivagal application of capsaicin (1% solution) is considered to cause a selective degeneration ... more Perivagal application of capsaicin (1% solution) is considered to cause a selective degeneration of vagal afferent C fibres and has been used extensively to examine the site of action of many gastrointestinal (GI) neuropeptides. The actions of both capsaicin and GI neuropeptides may not be restricted to vagal afferent fibres, however, as other non-sensory neurones have displayed sensitivity to capsaicin and brainstem microinjections of these neuropeptides induce GI effects similar to those obtained upon systemic application. The aim of the present study was to test the hypothesis that perivagal capsaicin induces degeneration of vagal efferents controlling GI functions. Experiments were conducted 7–14 days after 30 min unilateral perivagal application of 0.1–1% capsaicin. Immunohistochemical analyses demonstrated that, as following vagotomy, capsaicin induced dendritic degeneration, decreased choline acetyltransferase but increased nitric oxide synthase immunoreactivity in rat dorsal motor nucleus of the vagus (DMV) neurones. Electrophysiological recordings showed a decreased DMV input resistance and excitability due, in part, to the expression of a large conductance calcium-dependent potassium current and the opening of a transient outward potassium window current at resting potential. Furthermore, the number of DMV neurones excited by thyrotrophin-releasing hormone and the gastric motility response to DMV microinjections of TRH were decreased significantly. Our data indicate that perivagal application of capsaicin induced DMV neuronal degeneration and decreased vagal motor responses. Treatment with perivagal capsaicin cannot therefore be considered selective for vagal afferent C fibres and, consequently, care is needed when using perivagal capsaicin to assess the mechanism of action of GI neuropeptides.
flux. Conclusions: Ethanol alone does not stimulate autophagosome formation due to excessive LC3-... more flux. Conclusions: Ethanol alone does not stimulate autophagosome formation due to excessive LC3-II delipidation by Atg4. In contrast, ethanol+ low-dose CR pancreatitis decreases Atg4 and stimulates autophagy. Both ethanol and alcoholic pancreatitis cause lysosomal dysfunction resulting in impaired autophagic flux. The results support our "2-hit" hypothesis that a combination of 1) autophagy induction, and 2) lysosomal dysfunction causing impaired autophagic flux, are both critical in the mechanism of alcoholic pancreatitis.
Oxytocin (OXT) inputs to the dorsal vagal complex (DVC; nucleus of the tractus solitarius (NTS) d... more Oxytocin (OXT) inputs to the dorsal vagal complex (DVC; nucleus of the tractus solitarius (NTS) dorsal motor nucleus of the vagus (DMV) and area postrema) decrease gastric tone and motility. Our first aim was to investigate the mechanism(s) of OXT-induced gastric relaxation. We demonstrated recently that vagal afferent inputs modulate NTS–DMV synapses involved in gastric and pancreatic reflexes via group II metabotropic glutamate receptors (mGluRs). Our second aim was to investigate whether group II mGluRs similarly influence the response of vagal motoneurons to OXT. Microinjection of OXT in the DVC decreased gastric tone in a dose-dependent manner. The OXT-induced gastric relaxation was enhanced following bethanechol and reduced by l-NAME administration, suggesting a nitrergic mechanism of gastroinhibition. DVC application of the group II mGluR antagonist EGLU induced a gastroinhibition that was not dose dependent and shifted the gastric effects of OXT to a cholinergic-mediated mechanism. Evoked and miniature GABAergic synaptic currents between NTS and identified gastric-projecting DMV neurones were not affected by OXT in any neurones tested, unless the brainstem slice was (a) pretreated with EGLU or (b) derived from rats that had earlier received a surgical vagal deafferentation. Conversely, OXT inhibited glutamatergic currents even in naive slices, but their responses were unaffected by EGLU pretreatment. These results suggest that the OXT-induced gastroinhibition is mediated by activation of the NANC pathway. Inhibition of brainstem group II mGluRs, however, uncovers the ability of OXT to modulate GABAergic transmission between the NTS and DMV, resulting in the engagement of an otherwise silent cholinergic vagal neurocircuit.
Recent studies have shown that pancreatic exocrine secretions (PES) are modulated by dorsal motor... more Recent studies have shown that pancreatic exocrine secretions (PES) are modulated by dorsal motor nucleus of the vagus (DMV) neurones, whose activity is finely tuned by GABAergic and glutamatergic synaptic inputs. Group II metabotropic glutamate receptors (mGluR) decrease synaptic transmission to pancreas-projecting DMV neurones and increase PES. In the present study, we used a combination of in vivo and in vitro approaches aimed at characterising the effects of caerulein-induced acute pancreatitis (AP) on the vagal neurocircuitry modulating pancreatic functions. In control rats, microinjection of bicuculline into the DMV increased PES, whereas microinjections of kynurenic acid had no effect. Conversely, in AP rats, microinjection of bicuculline had no effect, whereas kynurenic acid decreased PES. DMV microinjections of the group II mGluR agonist APDC and whole cell recordings of excitatory currents in identified pancreas-projecting DMV neurones showed a reduced functional response in AP rats compared to controls. Moreover, these changes persisted up to 3 weeks following the induction of AP. These data demonstrate that AP increases the excitatory input to pancreas-projecting DMV neurones by decreasing the response of excitatory synaptic terminals to group II mGluR agonist.
The nucleus tractus solitarius (NTS) receives visceral information from the gastrointestinal, car... more The nucleus tractus solitarius (NTS) receives visceral information from the gastrointestinal, cardiovascular and respiratory systems via type-A and type-C fibers. NTS nucleus centralis (cNTS) recei...
Endoscopic retrograde cholangiopancreatography (ERCP) is a procedure used to identify biliary duc... more Endoscopic retrograde cholangiopancreatography (ERCP) is a procedure used to identify biliary duct obstruction. 5-10% of patients, however, develop acute pancreatitis (AP). AP is a severe disorder ...
Perivagal application of capsaicin (1% solution) is considered to cause a selective degeneration ... more Perivagal application of capsaicin (1% solution) is considered to cause a selective degeneration of vagal afferent C fibres and has been used extensively to examine the site of action of many gastrointestinal (GI) neuropeptides. The actions of both capsaicin and GI neuropeptides may not be restricted to vagal afferent fibres, however, as other non-sensory neurones have displayed sensitivity to capsaicin and brainstem microinjections of these neuropeptides induce GI effects similar to those obtained upon systemic application. The aim of the present study was to test the hypothesis that perivagal capsaicin induces degeneration of vagal efferents controlling GI functions. Experiments were conducted 7–14 days after 30 min unilateral perivagal application of 0.1–1% capsaicin. Immunohistochemical analyses demonstrated that, as following vagotomy, capsaicin induced dendritic degeneration, decreased choline acetyltransferase but increased nitric oxide synthase immunoreactivity in rat dorsal motor nucleus of the vagus (DMV) neurones. Electrophysiological recordings showed a decreased DMV input resistance and excitability due, in part, to the expression of a large conductance calcium-dependent potassium current and the opening of a transient outward potassium window current at resting potential. Furthermore, the number of DMV neurones excited by thyrotrophin-releasing hormone and the gastric motility response to DMV microinjections of TRH were decreased significantly. Our data indicate that perivagal application of capsaicin induced DMV neuronal degeneration and decreased vagal motor responses. Treatment with perivagal capsaicin cannot therefore be considered selective for vagal afferent C fibres and, consequently, care is needed when using perivagal capsaicin to assess the mechanism of action of GI neuropeptides.
flux. Conclusions: Ethanol alone does not stimulate autophagosome formation due to excessive LC3-... more flux. Conclusions: Ethanol alone does not stimulate autophagosome formation due to excessive LC3-II delipidation by Atg4. In contrast, ethanol+ low-dose CR pancreatitis decreases Atg4 and stimulates autophagy. Both ethanol and alcoholic pancreatitis cause lysosomal dysfunction resulting in impaired autophagic flux. The results support our "2-hit" hypothesis that a combination of 1) autophagy induction, and 2) lysosomal dysfunction causing impaired autophagic flux, are both critical in the mechanism of alcoholic pancreatitis.
Oxytocin (OXT) inputs to the dorsal vagal complex (DVC; nucleus of the tractus solitarius (NTS) d... more Oxytocin (OXT) inputs to the dorsal vagal complex (DVC; nucleus of the tractus solitarius (NTS) dorsal motor nucleus of the vagus (DMV) and area postrema) decrease gastric tone and motility. Our first aim was to investigate the mechanism(s) of OXT-induced gastric relaxation. We demonstrated recently that vagal afferent inputs modulate NTS–DMV synapses involved in gastric and pancreatic reflexes via group II metabotropic glutamate receptors (mGluRs). Our second aim was to investigate whether group II mGluRs similarly influence the response of vagal motoneurons to OXT. Microinjection of OXT in the DVC decreased gastric tone in a dose-dependent manner. The OXT-induced gastric relaxation was enhanced following bethanechol and reduced by l-NAME administration, suggesting a nitrergic mechanism of gastroinhibition. DVC application of the group II mGluR antagonist EGLU induced a gastroinhibition that was not dose dependent and shifted the gastric effects of OXT to a cholinergic-mediated mechanism. Evoked and miniature GABAergic synaptic currents between NTS and identified gastric-projecting DMV neurones were not affected by OXT in any neurones tested, unless the brainstem slice was (a) pretreated with EGLU or (b) derived from rats that had earlier received a surgical vagal deafferentation. Conversely, OXT inhibited glutamatergic currents even in naive slices, but their responses were unaffected by EGLU pretreatment. These results suggest that the OXT-induced gastroinhibition is mediated by activation of the NANC pathway. Inhibition of brainstem group II mGluRs, however, uncovers the ability of OXT to modulate GABAergic transmission between the NTS and DMV, resulting in the engagement of an otherwise silent cholinergic vagal neurocircuit.
Recent studies have shown that pancreatic exocrine secretions (PES) are modulated by dorsal motor... more Recent studies have shown that pancreatic exocrine secretions (PES) are modulated by dorsal motor nucleus of the vagus (DMV) neurones, whose activity is finely tuned by GABAergic and glutamatergic synaptic inputs. Group II metabotropic glutamate receptors (mGluR) decrease synaptic transmission to pancreas-projecting DMV neurones and increase PES. In the present study, we used a combination of in vivo and in vitro approaches aimed at characterising the effects of caerulein-induced acute pancreatitis (AP) on the vagal neurocircuitry modulating pancreatic functions. In control rats, microinjection of bicuculline into the DMV increased PES, whereas microinjections of kynurenic acid had no effect. Conversely, in AP rats, microinjection of bicuculline had no effect, whereas kynurenic acid decreased PES. DMV microinjections of the group II mGluR agonist APDC and whole cell recordings of excitatory currents in identified pancreas-projecting DMV neurones showed a reduced functional response in AP rats compared to controls. Moreover, these changes persisted up to 3 weeks following the induction of AP. These data demonstrate that AP increases the excitatory input to pancreas-projecting DMV neurones by decreasing the response of excitatory synaptic terminals to group II mGluR agonist.
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Papers by Tanja Babic