The mechanism by which pancreatitis causes pain is unknown. The neuropeptide calcitonin gene-related peptide (CGRP) is released after sensory nerve activation and promotes nociceptive signaling in models of visceral pain. We hypothesized that acute pancreatitis leads to the activation of pancreatic sensory neurons that release CGRP in the dorsal horn of the spinal cord. This signal is ultimately transmitted to the brain, and pain is sensed.
To induce pancreatitis, rats were injected with l-arginine (500 mg/kg) intraperitoneally or saline (control). Pancreatitis was confirmed by measuring serum amylase and evaluating pancreatic histology. Activation of nociceptive pathways was evaluated by counting Fos-like immunoreactive nuclei (FLI) in the dorsal horn of the spinal cord at T3-L1. Some animals received the CGRP antagonist CGRP(8-37) (50 microg intrathecally) 2 hours before perfusion. Animals were compared using a 2-tailed t test.
l-Arginine treatment induced acute necrotizing pancreatitis in the rat at 24 hours. l-Arginine (24 hours) increased FLI in the dorsal horn of the spinal cord, with a peak effect at L1. Intrathecal administration of CGRP(8-37) significantly decreased the number of FLI nuclei in the dorsal horn of the spinal cord in T11-L1.
Nociception in the l-arginine model of acute pancreatitis is partially mediated by the release of CGRP in the dorsal horn of the spinal cord. Antagonism of CGRP or its receptors may be useful in treating pain from acute pancreatitis.
"There were also marked increases in the intensity of CGRP nerve fibers in L1 and S1 spinal cord. The changes in CGRP protein but not mRNA in the spinal cord during colitis may be due to the following biological processes: 1) an anterograde transport of CGRP from DRG to the spinal cord (Kashihara et al., 1989; Schäfers et al., 2002); 2) release of CGRP from the nerve terminals (Wick et al., 2006; Eberhardt et al., 2008; Merighi et al., 2008); and 3) degradation of CGRP once it binds to receptor (Padilla et al., 2007). The later may cause intracellular signaling kinase activation such as increases in Akt phosphorylation in these spinal segments. "
[Show abstract][Hide abstract] ABSTRACT: Previous study has shown that colitis-induced increases in calcitonin gene-related peptide (CGRP) immunoreactivity in bladder afferent neurons result in sensory cross-sensitization. To further determine the effects of colitis on CGRP expression in neurons other than bladder afferents, we examined and compared the levels of CGRP mRNA and immunoreactivity in the lumbosacral dorsal root ganglia (DRG) and spinal cord before and during colitis in rats. We also examined the changes in CGRP immunoreactivity in colonic afferent neurons during colitis. Results showed increases in CGRP mRNA levels in L1 (2.5-fold, p<0.05) and S1 DRG (1.9-2.4-fold, p<0.05). However, there were no changes in CGRP mRNA levels in L1 and S1 spinal cord during colitis. CGRP protein was significantly increased in L1 (2.5-fold increase, p<0.05) but decreased in S1 (50% decrease, p<0.05) colonic afferent neurons, which may reflect CGRP release from these neurons during colitis. In L1 spinal cord, colitis caused increases in the number of CGRP nerve fibers in the deep lamina region extending to the gray commissure where the number of phospho-Akt neurons was also increased. In S1 spinal cord, colitis caused the increases in the intensity of CGRP fibers in the regions of dorso-lateral tract, and caused the increases in the level of phospho-Akt in the superficial dorsal horn of the spinal cord. In spinal cord slice culture, exogenous CGRP increased the phosphorylation level of Akt but not the phosphorylation level of extracellular-signal regulated kinase ERK1/2 even though our previous studies showed that colitis increased the phosphorylation level of ERK1/2 in L1 and S1 spinal cord. These results suggest that CGRP is synthesized in the DRG and may transport to the spinal cord where it initiates signal transduction during colitis.
"It is possible that the GFLs are exerting their effects on the enhancement of release of iCGRP in sensory neurons through these GFRα receptors at this location during inflammation. There is direct evidence that CGRP is important in the propagation of the pain signal, since hyperalgesia due to both pancreatitis and inflammation induced by carrageenan is attenuated by a CGRP blocking antibody (Satoh et al., 1992; Wick et al., 2006). The GFRα receptors exist on motor neurons originating in the ventral horn of the spinal cord (Homma et al., 2003) and these neurons also can contain CGRP (Gibson et al., 1988;Kruger et al., 1988). "
[Show abstract][Hide abstract] ABSTRACT: The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are a group of peptides that have been implicated as important factors in inflammation, since they are released in increased amounts during inflammation and induce thermal hyperalgesia upon injection. Mouse isolated sensory neurons in culture and freshly dissociated spinal cord slices were used to examine the enhancement in stimulated-release of the neuropeptide, calcitonin gene-related peptide (CGRP), as a measure of sensitization. Exposure of isolated sensory neurons in culture to GDNF, neurturin, and artemin enhanced the capsaicin-stimulated release of immunoreactive calcitonin gene-related peptide (iCGRP) two- to threefold, but did not increase potassium-stimulated release of iCGRP. A similar profile of sensitization was observed in freshly dissociated spinal cord slices. Persephin, another member of the GFL family thought to be important in development, was unable to induce an enhancement in the release of iCGRP. These results demonstrate that specific GFLs are important mediators affecting sensory neuronal sensitivity, likely through modulation of the capsaicin receptor. The sensitization of sensory neurons during inflammation, and the pain and neurogenic inflammation resulting from this sensitization, may be due in part to the effects of these selected GFLs.
[Show abstract][Hide abstract] ABSTRACT: In this paper, the design and characterization of a 7-bit CMOS
stochastic-flash analog-to-digital converter is illustrated by means of
simulations including level-3 CMOS models and estimated dither-based
spectra. The conversion scheme and its main properties are briefly
recalled, and a possible design of the voltage reference generator
proposed. It is shown that mismatches among the resistors in the ladder
employed to generate these voltages are largely compensated by the
presented architecture when small-scale dithering is employed
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