Acute pancreatitis decreases the sensitivity of pancreas‐projecting dorsal motor nucleus of the vagus neurones to group II metabotropic glutamate receptor agonists in rats

Abstract

Key pointsr Acute pancreatitis is one of the most severe disorders of the exocrine pancreas. r Pancreatic exocrine secretions (PES) are under regulatory control of dorsal motor nucleus of the vagus (DMV) neurones and their activity is regulated by inhibitory GABAergic and excitatory glutamatergic synaptic inputs.r Group II metabotropic glutamate receptors (mGluR) decrease synaptic transmission to pancreas-projecting DMV neurones and modulate PES.r In this study, we show that acute pancreatitis induces a long-lasting increase in excitatory synaptic transmission to pancreas-projecting neurones by decreasing the response of excitatory synaptic terminals to group II mGluR agonists.r These data suggest that changes in group II mGluR expression in the DMV may underlie shortand long-term changes in PES in acute pancreatitis.Abstract 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.

Neural Control of the Pancreas

“…Specifically, we demonstrated that acute pancreatitis decreases the response of glutamatergic synaptic terminals in the DMV to group II mGluR agonist. In contrast, group III mGluRs do not appear to be affected by acute pancreatitis (9). These findings suggest that acute pancreatitis selectively affects DMV neurons involved in the regulation of pancreatic exocrine secretion and further supports the notion that exocrine and endocrine pancreatic secretions are regulated by separate neuronal populations.…”

“…Although glutamate is one of the principal neurotransmitters in synapses impinging onto pancreas-projecting DMV neurons, it does not appear to exert a major role on pancreatic functions under control conditions. In fact, microinjections of ionotropic glutamate receptor antagonist kynurenic acid into the DMV do not affect pancreatic exocrine secretion in control rats (9). However, glutamatergic synapses impinging on pancreas-projecting DMV neurons are subject to modulation by various neurotransmitters and hormones (10).…”

“…Parasympathetic pathways innervating the pancreas. Abbreviations: Area postrema (AP), Arcuate Nucleus (ARC),Bed nucleus of the stria terminalis (BNST), Dorsomedial nucleus of the hypothalamus (DMH), Dorsal motor nucleus of the vagus (DMV), Lateral hypothalamic area (LHA), Medial preoptic area (MPO), Nucleus of the tractus solitarius (NTS), Organum vasculosum of the lamina terminalis (OVLT), Prefrontal cortex (PFC), Paraventricular nucleus (PVN), Retrochiasmatic area (RCA), Suprachiasmatic nucleus (SCN), Subfornical organ (SFO), Ventromedial hypothalamus (VMH),microinjections of the GABA A receptor antagonist bicuculline increase pancreatic exocrine secretion(9).…”

Presynaptic ionotropic glutamate receptors modulate GABA release in the mouse dorsal motor nucleus of the vagus

“…Thus, drug effects on mIPSC frequency, especially in the absence of effects on amplitude, were interpreted to be due to actions at receptors located on or near synaptic terminals. Presynaptic modulation of GABA or glutamate release mediated by mGluRs in the DMV and NTS have been described (Jin et al, 2004, Browning and Travagli, 2007, Babic et al, 2012, Babic and Travagli, 2014), but functional iGluR activity at synaptic terminals contacting DMV neurons has been suggested only indirectly. A previous report suggested the presence of iGluRs on GABA terminals in the DMV, but did not identify which receptor types were involved in the response (Derbenev et al, 2006).…”

“…In addition, glutamate binds metabotropic glutamate receptors (mGluR) in the DMV to modulate responsiveness of GABAergic presynaptic terminals (Browning et al, 2006, Browning and Travagli, 2007, Babic et al, 2012, Babic and Travagli, 2014). In several brain regions, iGluRs on synaptic terminals (i.e., presynaptic receptors) have been identified functionally as autoreceptors to modulate glutamate release or heteroreceptors to alter GABA release (Berretta and Jones, 1996, Liu et al, 1999, Duguid and Smart, 2004).…”