Role of the vagus in the reduced pancreatic exocrine function in copper-deficient rats

Abstract

Copper plays an essential role in the function and development of the central nervous system and exocrine pancreas. Dietary copper limitation is known to result in noninflammatory atrophy of pancreatic acinar tissue. Our recent studies have suggested that vagal motoneurons regulate pancreatic exocrine secretion (PES) by activating selective subpopulations of neurons within vagovagal reflexive neurocircuits. We used a combination of in vivo, in vitro, and immunohistochemistry techniques in a rat model of copper deficiency to investigate the effects of a copper-deficient diet on the neural pathways controlling PES. Duodenal infusions of Ensure or casein, as well as microinjections of sulfated CCK-8, into the dorsal vagal complex resulted in an attenuated stimulation of PES in copper-deficient animals compared with controls. Immunohistochemistry of brain stem slices revealed that copper deficiency reduced the number of tyrosine hydroxylase-immunoreactive, but not neuronal nitric oxide synthase- or choline acetyltransferase-immunoreactive, neurons in the dorsal motor nucleus of the vagus (DMV). Moreover, a copper-deficient diet reduced the number of large (>11 neurons), but not small, intrapancreatic ganglia. Electrophysiological recordings showed that DMV neurons from copper-deficient rats are less responsive to CCK-8 or pancreatic polypeptide than are DMV neurons from control rats. Our results demonstrate that copper deficiency decreases efferent vagal outflow to the exocrine pancreas. These data indicate that the combined selective loss of acinar pancreatic tissue and the decreased excitability of efferent vagal neurons induce a deficit in the vagal modulation of PES.

Role of metabotropic glutamate receptors in the regulation of pancreatic functions

“…Finally, recent studies have also demonstrated in rats that copper deficiency, which causes a selective non inflammatory loss of pancreatic acinar tissue but leaves the islet of Langherans unaffected, diminishes the sensitivity of DMV neurons to CCK and PP, further supporting the notion that neurons responsive to these peptides specifically regulate PES [11]. These findings provide further evidence that pancreas-projecting DMV neurons comprise at least two subpopulations which modulate selectively exocrine or endocrine pancreatic functions.…”

“…Recent data from our laboratory have provided further evidence that separate vagal pathways regulate PES and insulin release and that DMV neurons regulating these two functions can be distinguished based on their neurochemical and pharmacological properties [1,9,11]. We have demonstrated that CCK, PP and GLP-1 have both presynaptic and postsynaptic effects on pancreas-projecting DMV neurons [9–12].…”

“…We have demonstrated that CCK, PP and GLP-1 have both presynaptic and postsynaptic effects on pancreas-projecting DMV neurons [9–12]. Furthermore, pancreas-projecting DMV neurons that respond to GLP-1 do not respond to PP or CCK [9,11], whereas the majority of DMV neurons that respond to CCK also respond to PP [11]. These data suggest that pancreas-projecting DMV neurons comprise at least two distinct neuronal subpopulations that respond either to GLP-1 or to CCK and PP.…”

Neural plasticity in pancreatitis and pancreatic cancer

“…Previous studies on the anatomy and physiology of pancreatic innervation under physiological conditions (Figure 1), during enteropancreatic reflex, exocrine section, digestive hormone effects, or during acute pancreatitis and pancreatic nociception in mice, have laid the foundations for our current understanding of neuroplasticity in all pancreatic disorders. [1][2][3][4][5][6][7][8] In ceruletide-induced acute pancreatitis in mice, sensory dorsal root ganglia (DRG) neurons upregulate pain-associated and inflammation-associated ion channels such as transient receptor potential cation channel subfamily V member 1 (TRPV1; also known as transient receptor potential vanilloid 1) or TRP cation channel subfamily A member 1 (TRPA1) within the first 24 h. 9 The activation of these ion channels is known to induce the release of substance P from the projections of these neurons in the spinal cord, and antegrade or antidromic release of substance P into the pancreas. Substance P was shown to be the major mediator of 'neurogenic' inflammation in the pancreas via recruitment of inflammatory cells to the tissue and enhancing fluid extravasation.…”

Acute pancreatitis decreases the sensitivity of pancreas‐projecting dorsal motor nucleus of the vagus neurones to group II metabotropic glutamate receptor agonists in rats

“…, b ; Babic et al . ) and microinjections of these agents into the dorsal vagal complex (DVC) elicit changes in PES and insulin release (Jung et al . ; Viard et al .…”