Functional gastrointestinal (GI) motility disorders, including functional dyspepsia, are very common, often chronic, and disabling conditions that account for a large proportion of consultations with primary care and specialist physicians. Despite the absence of anatomical GI abnormalities, patients with functional GI disorders suffer with varying bouts of unexplained pain, cramping, diarrhea, vomiting, and constipation.
The research laboratories of R. Alberto Travagli, Ph.D., and Kirsteen Browning, Ph.D., of Penn State Hershey Neural and Behavioral Sciences, focus on describing the pathophysiology of these disorders. Travagli and Browning have recently conducted a series of in vitro and in vivo experiments (in collaboration with Gregory Holmes, Ph.D.) designed to better describe the role of stress in causing the gastroparesis that often occurs in such disorders. Evidence from these experiments,
as well as from other laboratories, points toward stress related re-organization of the vagal sensory-motor loop connecting the gut to the central nervous system (CNS). The efferent limb of this reflex loop involves preganglionic parasympathetic neurons in the dorsal motor nucleus of the vagus (DMV), which provide the vagal output back to the GI tract. DMV neurons innervate postganglionic neurons located within the GI tract which belong to one of two distinct pathways; one is an excitatory pathway that increases gastric tone, motility and secretion via activation of muscarinic cholinergic receptors. The other is an inhibitory pathway that inhibits gastric functions mainly by releasing nitric oxide or vasoactive intestinal polypeptide.
Oxytocin is a well-recognized anti-stress neurohormone, and in the context of the vagal-GI loop, application of oxytocin recruits the DMV inhibitory pathway and causes vagally-mediated gastric relaxation. New evidence from the laboratories of Travagli and Browning, however, indicates that stress causes a change in the normal response to oxytocin, suggesting a rapid neural re-organization. In vitro, it was found that the stress hormone corticotrophin releasing factor (CRF) uncovered an inhibitory response to oxytocin in normal DMV neurons; this inhibitory response to oxytocin was observed in a rodent model of functional dyspepsia even in the absence of exogenously applied CRF. In vivo, injection of oxytocin in CNS vagal circuits induced gastric relaxation in the functional dyspepsia rodent model due to inhibition of the vagal excitatory pathway, in stark contrast to the relaxation observed in normal rodents which is mediated by excitatory of the vagal inhibitory pathway. Travagli says these data show that “brainstem homeostatic circuits are not the simple, static relay networks previously described,” but instead “adapt to ever-changing environmental conditions in a continuous and fluid manner and undergo short term adaptive plasticity”. In this way, vagally-regulated GI functions respond appropriately to a variety of intrinsic and extrinsic factors (e.g., stress, food, neurohormones,peripheral sensory inputs, time of day, etc.). In functional GI disorders, however, what may begin as adaptive neural re-organization instead goes awry, and may lead to chronic dysfunction.
These new data have been submitted for presentation at the April 2012 annual meeting for Experimental Biology to be held in San Diego, California. The Travagli and Browning laboratories, funded by both the National Institutes of Health (NIH) and the National Science Foundation (NSF), are now investigating the mechanisms involved in the reorganization of neural substrates in not only functional dyspepsia, but also acute pancreatitis, hyperglycemia and maternal obesity.