Gastrointestinal (GI) dysfunction is one of the permanent quality of life challenges facing the individual following spinal cord injury SCI (Gore et al., 1981; Berlly and Wilmot, 1984; Anderson, 2004; Simpson et al., 2012). Beyond the alimentary canal, the gastrointestinal tract of humans includes accessory organs (e.g. liver, pancreas and gall bladder) necessary for digestion that are also prone to dysregulation in response to the profound systemic changes in physiology after SCI.

The pancreas can be functionally divided into endocrine and exocrine compartments. The former secretes insulin, glucagon, somatostatin and pancreatic polypeptide into the circulation while the later secretes digestive enzymes into the small intestine though the common bile-pancreatic duct terminating in the duodenum. Whereas the endocrine pancreas is integral for metabolic homeostasis, pancreatic exocrine secretions (PES) are essential for proper GI function, including digestion and elimination of undigested fecal matter (reviewed in Zhang et al., 2022). Most of the pancreatic mass is exocrine tissue; acinar cells make up 82 % of the pancreas volume while 2 % of the pancreas is comprised of endocrine pancreatic islets and α-cells (Bolender, 1974). The acinar cells are responsible for producing the precursor and active enzymes that enter the duodenum for digestion including trypsinogen, α-amylase, and lipase that break down proteins, carbohydrates, and fats to be absorbed by the duodenum and other regions of the small intestine (Doyle et al., 2012; Petersen, 2018). Each of these secretory functions have long been recognized to include multimodal central control by enteric circuits, sympathetic splanchnic innervation from the T6-L2 intermediolateral spinal cord as well as parasympathetic vago-vagal reflexes centered within the dorsal vagal complex (DVC) within the medulla (Ionescue et al., 1983; Rinaman and Miselis, 1987; Viard et al., 2007; Mussa and Verberne, 2008; Mussa et al., 2011; Rodriguez-Diaz and Caicedo, 2014; Makhmutova and Caicedo, 2021; Wulf and Tom, 2023).

Pancreatic dysfunction is one recognized, yet poorly understood comorbidity in the SCI population (Carey et al., 1977; Gore et al., 1981; Nobel et al., 2002; Bigford et al., 2013; Pirolla et al., 2014; Gordon et al., 2021; Ho et al., 2021). Whereas dysregulated glycemic control after SCI is frequently manifested as Type-2 diabetes (Gordon et al., 2021), the main symptom of exocrine pancreatic insufficiency (EPI) is malnutrition as the result of inadequate digestion, dysregulated bicarbonate secretion and malabsorption; particularly of lipids (Struyvenberg et al., 2017). Specifically, SCI individuals present pancreatic dysregulation in the form of cholestasis, when bile flow from the liver is impeded thereby leading to reduced fat emulsification (steatorrhea), acute pancreatitis, and high levels of serum pancreatic enzymes (Carey et al., 1977; Nobel et al., 2002; Pirolla et al., 2014). Unlike other populations with pancreatic dysfunction, individuals with SCI lack visceral nociceptive sensation; particularly following higher level (ca. T5 and above) spinal lesions (Pirolla et al., 2014). Therefore, diminished perception of the classic symptoms of pancreatic dysfunction, such as recurring or persistent abdominal pain, results in pancreatic dysfunction and pathologies that often go undiagnosed in the SCI population. Although the pancreas plays a crucial role in GI function, preclinical studies of the effects of SCI on pancreatic integrity are limited (Bigford et al., 2013).

We have recently reported increased intestinal barrier permeability in a rat model of high thoracic (T3) SCI that is most pronounced in the duodenum (Radler et al., 2024). The increased barrier permeability, resulting bacterial translocation, acute pancreatitis and high levels of serum pancreatic enzymes that are associated with SCI (Gore et al., 1981; Pirolla et al., 2014) are consistent with over-secretion of pancreatic enzymes. The first aim of our study was to validate the basal dysregulation of PES in our established T3-SCI rat model.

Central administration of cholecystokinin (CCK; Chey and Chang, 2001) and thyrotropin releasing hormone (TRH; Okumura et al., 1995) stimulate pancreatic exocrine secretion as does ghrelin (Li et al., 2006). However, our previous reports indicate that experimental SCI reduces vagally-mediated sensitivity to GI peptides that regulate gastric reflexes such as CCK (Tong et al., 2011) and ghrelin (Besecker et al., 2018) and that the reduced sensitivity to CCK and mechanical stretch of the stomach wall involves vagal afferents (Besecker et al., 2020). The afferent nature of pancreatic vagal firing has also been reported (Mussa et al., 2008). Therefore, the second aim of our study was to quantify the dysregulation of PES in response to a physiologically- and clinically-relevant stimulus in the form of a enterally administered mixed nutrient meal.

Finally, pharmacological activation of vagal efferent discharge with TRH has been demonstrated in numerous studies of intact experimental models and remains unaffected by experimental SCI (Swartz and Holmes, 2014). The final aim of our study was to pharmacologically quantify the integrity of the efferent limb of the vago-vagal circuitry driving pancreatic secretions.