Effects of brain stem cholecystokinin-8s on gastric tone and esophageal-gastric reflex

Abstract

Holmes GM, Tong M, Travagli RA. Effects of brain stem cholecystokinin-8s on gastric tone and esophageal-gastric reflex. Am J Physiol Gastrointest Liver Physiol 296: G621-G631, 2009. First published January 8, 2009 doi:10.1152/ajpgi.90567.2008.-The actions of cholecystokinin (CCK) on gastrointestinal functions occur mainly via paracrine effects on peripheral sensory vagal fibers, which engage vago-vagal brain stem circuits to convey effector responses back to the gastrointestinal tract. Recent evidence suggests, however, that CCK also affects brain stem structures directly. Many electrophysiological studies, including our own, have shown that brain stem vagal circuits are excited by sulfated CCK (CCK-8s) directly, and we have further demonstrated that CCK-8s induces a remarkable degree of plasticity in GABAergic brain stem synapses. In the present study, we used fasted, anesthetized Sprague-Dawley rats to investigate the effects of brain stem administration of CCK-8s on gastric tone before and after activation of the esophageal-gastric reflex. CCK-8s microinjected in the dorsal vagal complex (DVC) or applied on the floor of the fourth ventricle induced an immediate and transient decrease in gastric tone. Upon recovery of gastric tone to baseline values, the gastric relaxation induced by esophageal distension was attenuated or even reversed. The effects of CCK-8s were antagonized by vagotomy or fourth ventricular, but not intravenous, administration of the CCK-A antagonist lorglumide, suggesting a central, not peripheral, site of action. The gastric relaxation induced by DVC microinjection of CCK-8s was unaffected by pretreatment with systemic bethanecol but was completely blocked by N G -nitro-L-arginine methyl ester, suggesting a nitrergic mechanism of action. These data suggest that 1) brain stem application of CCK-8s induces a vagally mediated gastric relaxation; 2) the CCK-8s-induced gastric relaxation is mediated via activation of nonadrenergic, noncholinergic pathways; and 3) CCK-8s reverses the esophageal-gastric reflex transiently.vago-vagal reflexes; gastric reflexes ESOPHAGEAL DISTENSION has long been recognized to elicit a robust and reflexive gastric relaxation (21). Early models of gastrointestinal vago-vagal reflexes presented a framework to explain many of the features of the brain stem circuits devoted to gastric reflex control, whereby stimulation of sensory vagal afferent fibers activates second-order neurons of the nucleus tractus solitarii (NTS). Subsequently, these second-order neurons modulate the output of preganglionic neurons in the dorsal motor nucleus of the vagus (DMV) that, in turn, control gastric functions to complete the vago-vagal loop (reviewed in Ref. 72).The esophageal-gastric reflex (or receptive relaxation) decreases gastric tone and allows swallowed food to be transported to the stomach with a minimal increase in intragastric pressure. Neurophysiological studies by Jean first showed the association of neurons of the caudal brain stem with esophageal function (reviewed in Re...

Experimental spinal cord injury in rats diminishes vagally-mediated gastric responses to cholecystokinin-8s

“…We have previously demonstrated that central administration of CCK-8s to the DVC induces gastric relaxation. Specifically, the gastroinhibitory effect of 450 pmol CCK-8s microinjection into the DVC was eliminated by vagotomy and systemic pretreatment with the nitric oxide synthase inhibitor L-NAME 18. These data demonstrated that the effects of central CCK-8s microinjection are vagally-mediated and include a postganglionic NANC pathway.…”

“…CCK release has profound effects on gastrointestinal functions 9-11, its vagal mechanisms of action include a paracrine activation of vagal afferent fibers along the gut wall (reviewed in 12) as well as direct actions upon nodose ganglion 13,14, and DVC neurons 15-18.…”

Vanilloid, purinergic, and CCK receptors activate glutamate release on single neurons of the nucleus tractus solitarius centralis

“…The main support for this mechanism of action derives from the observation that capsaicin treatment, either systemic, perivagal, or directly to the intestinal mucosa, attenuates or abolishes the effects of systemic administration of CCK on functional gastric and pancreatic parameters (33,34,42,46). Behavioral, electrophysiological and pharmacological studies from many groups, including our own, strongly suggest that the effects of CCK may not be limited to a paracrine mechanism of action, however, and effects at other sites, including direct actions on central vagal brainstem circuits, must be considered (5,9,10,16,27,43,56). The second aim of this study was to investigate whether CCK-sensitive afferent inputs to cNTS neurons are, indeed, C-fibers and are therefore responsive to the vanilloid agonist capsaicin but insensitive to purinergic agonists.…”

Vagal neurocircuitry and its influence on gastric motility

“…3). A hormonal effect of CCK on DVC neurons is probable; in rats, brainstem microinjections of CCK8s decrease gastric tone and motility, reduce the gastric response to oesophageal distention (the RRR) 133 and increase pancreatic exocrine secretion 118 . Underestimating the potentially adverse effects of capsaicin on vagal efferent function would, therefore, lead to overestimation of the vagal afferent contribution to the actions of CCK and other gastrointestinal neuropeptides.…”