Pancreatic insulin and exocrine secretion are under the modulatory control of distinct subpopulations of vagal motoneurones in the rat

Abstract

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.