Expression of NK-1 and NK-3 tachykinin receptors in pancreatic acinar cells after acute experimental pancreatitis in rats

Abstract

Activation of neurokinin (NK)-1 receptors but not of NK-3 stimulates amylase release from isolated pancreatic acini of the rat. Immunofluorescence studies show that NK-1 receptors are more strongly expressed than NK-3 receptors on pancreatic acinar cells under basal conditions. No studies have examined the expression of the two NK receptor populations in pancreatic acini during pancreatitis in rats. We therefore investigated the relationships between expression of these two tachykinin receptors and experimental acute pancreatitis induced by stimulating pancreatic amylase with caerulein (CK) in rats. Hyperstimulation of the pancreas by CK caused an increase in plasma amylase and pancreatic water content and resulted in morphological evidence of cytoplasmic vacuolization. Immunofluorescence analysis revealed a similar percentage of NK-1 receptor antibody immunoreactive acinar cells in rats with pancreatitis and in normal rat tissue but a larger percentage of NK-3 receptor immunoreactive cells in acute pancreatitis than in normal pancreas. Western blot analysis of NK-1 and NK-3 receptor protein levels after CK-induced pancreatitis showed no change in NK-1 receptors but a stronger increase in NK-3 receptor expression in pancreatic acini compared with normal rats thus confirming the immunofluorescence data. These new findings support previous evidence that substance P-mediated functions within the pancreas go beyond sensory signal transduction contributing to neurogenic inflammation, and they suggest that substance P plays a role in regulating pancreatic exocrine secretion via acinar NK-1 receptors. The significant increase in NK-3 receptors during pancreatic stimulation suggests that NK-3 receptors also intervene in the pathogenesis of mild acute pancreatitis in rats. isolated pancreatic acini; tachykinin receptor distribution; immunofluorescence; Western blot analysis THE NEUROPEPTIDES substance P (SP), neurokinin (NK)-A, and NK-B are primary mammalian tachykinins (TKs) involved in a wide-ranging control of peripheral and central functional activities. Each TK preferentially binds to a specific cell surface receptor subtype belonging to the superfamily of G proteincoupled receptors: SP binds to the NK-1 receptor, NK-A to the NK-2 receptor, and NK-B to the NK-3 receptor. TKs and their receptors are diffusely distributed in the mammalian gastrointestinal tract where they mediate motor, secretory, and circulatory responses (10).To date, few reports exist on the role of the TKs in regulating exocrine pancreatic secretion. TKs acting on NK-1 and NK-2 receptors have been reported to stimulate in vitro pancreatic amylase secretion (12-14, 16, 20, 33), and NK-1 and NK-2 receptors have been detected in the pancreatic acinar cells of guinea pig and mouse (6,11,29,30,32). No information is available on whether acinar cells in the pancreas of these and other animal species express the NK-3 receptor, and little is known on the effects of NK-3 receptor agonists on pancreatic exocrine secretion (7,12,18,20,33). In our recent stud...

Molecular mechanisms of pain in acute pancreatitis: recent basic research advances and therapeutic implications

“…In AP patients, the expression levels of the SP and NK1R were greatly increased in the necrotic regions and adjacent inflamed regions of the pancreas, compared to normal controls ( Han et al, 2021 ). Similar findings were observed in pancreatic tissues from the experimental model of AP in mice ( Bhatia et al, 1998 ; Broccardo et al, 2006 ). Up-regulated Nk1r and Ppt-a mRNA expression and SP was found in isolated mouse PACs treated with cerulein ( Koh et al, 2010 ), a cholecystokinin (CCK) analog commonly used to induce AP model via stimulating CCK1 receptor ( Yang et al, 2020 ).…”

Substance P Activates Both Contractile and Inflammatory Pathways in Lymphatics Through the Neurokinin Receptors NK1R and NK3R

“…Another question is whether these functions are linked in order to heal, or does SP activation/contraction lead to lymphatic dysfunction? From the literature, it is evident that SP has been extensively described to be an important mediator of inflammatory responses and pathological conditions associated with inflammation, including allergic contact dermatitis, inflammatory bowel disease, rheumatoid arthritis and pancreatitis [38,36,53,6]. SP is released from C‐sensory fibers that have been shown to be involved in neurogenic inflammation and SP has been implicated as one of the agents responsible for vasodilation and plasma extravasation under these conditions [4,20].…”

Cardiocirculatory pathophysiological mechanisms in severe acute pancreatitis

“…All these mechanisms contribute to amplify the inflammatory and systemic manifestation of AP [44] . Furthermore, SP could mediate the inflammatory response by directly activating tachykinin receptors in pancreatic acinar cells, leading to release of both enzyme and inflammatory mediators from these cells [45,46] . In this early phase of AP, acinar cells would be the pri mary source of inflammatory mediators and the relative im balance between pro-inflammatory and anti-inflammatory responses could be the crucial issue for the progression and severity of the disease [44] .…”