• The pancreas consists of two functional parts, exocrine, which releases digestive enzymes, and endocrine, which releases hormones, such as insulin. • Both parts are under neural regulatory control by the vagus nerve. Vago-vagal neurocircuits integrate the sensory information, chemical or mechanical, from the gastrointestinal tract with the motor output back to the gastrointestinal system, including the pancreas. • Both excitatory and inhibitory vago-vagal neural circuits are regulated by many neurotransmitters, including glutamate acting on different types of metabotropic glutamate receptors. • In this study, we show that different subtypes of metabotropic glutamate receptors regulate differentially exocrine and endocrine pancreatic functions by affecting different neurocircuits. • The present study provides the physiological basis to develop pharmacological strategies aimed to provide a better understanding of pathophysiological conditions, such as pancreatitis or diabetes, that affect selectively the exocrine or endocrine pancreas. Brainstem vago-vagal neurocircuits modulate upper gastrointestinal functions. Derangement of these sensory-motor circuits is implicated in several pathophysiological states, such as gastroesophageal reflux disease (GERD), functional dyspepsia and, possibly, pancreatitis. While vagal circuits controlling the stomach have received more attention, the organization of brainstem pancreatic neurocircuits is still largely unknown. We aimed to investigate the in vitro and in vivo modulation of brainstem vagal circuits controlling pancreatic secretion. Using patch clamp techniques on identified vagal pancreas-projecting neurones, we studied the effects of metabotropic glutamate receptor (mGluR) agents in relation to the effects of exendin-4, a glucagon-like peptide 1 analogue, cholecystokinin (CCK) and pancreatic polypeptide (PP). An in vivo anaesthetized rat preparation was used to measure pancreatic exocrine secretion (PES) and plasma insulin following microinjection of metabotropic glutamate receptor (mGluR) agonists and exendin-4 in the brainstem. Group II and III mGluR agonists (2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) and l(+)-2-amino-4-phosphonobutyric acid (l-AP4), respectively) decreased the frequency of miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSCs, respectively) in the majority of the neurones tested. All neurones responsive to l-AP4 were also responsive to APDC, but not vice versa. Further, in neurones where l-AP4 decreased mIPSC frequency, exendin-4 increased, while PP had no effect upon, mIPSC frequency. Brainstem microinjection of APDC or l-AP4 decreased plasma insulin secretion, whereas only APDC microinjections increased PES. Exendin-4 microinjections increased plasma insulin. Our results indicate a discrete organization of vagal circuits, which opens up promising avenues of research aimed at investigating the physiology of homeostatic autonomic neurocircuits.
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