Pancreatic Neuropathy and Neuropathic Pain—A Comprehensive Pathomorphological Study of 546 Cases

Ceyhan, Güralp O.; Bergmann, Frank; Kadıhasanoğlu, Mustafa; Altıntaş, Burak; Demir, Ihsan Ekin; Hinz, Ulf; Müller, Michael; Giese, Thomas; Büchler, Markus W.; Giese, Nathalia A.; Frieß, Helmut

doi:10.1053/j.gastro.2008.09.029

Cited by 330 publications

(347 citation statements)

References 39 publications

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“…8,10,33,58 In addition, recent studies support the idea that the peripheral immune system and spinal microglia are crucial in the generation of neuropathic pain. 35,37,58 The contribution of fractalkine to general neuropathic pain was shown earlier: In several experimental models of neuropathic pain, it was shown that endogenous fractalkine is released by DRG and is accompanied by the upregulation of CX3CR1 in the spinal microglia and neuropathic pain behavior. 12,14,23,24,38,39 Similar effects were observed when fractalkine was administered exogenously.…”

Section: Discussionmentioning

confidence: 86%

“…34 Although pain in CP would traditionally be classified as inflammatory pain, recent studies pointed to the simultaneous presence of structural changes in axons and ganglia in CP, thus implying the involvement of a concomitant neuropathic component. 35,36,58 Previous studies have determined that the 'inflammatory' and the 'neuropathic' component of pain in CP may not be independent but instead closely linked: The 'neuro-immune crosstalk' through pancreatic neuritis, and changes in intrapancreatic neural plasticity were all associated with the severity of pain experienced by CP patients. 8,10,33,58 In addition, recent studies support the idea that the peripheral immune system and spinal microglia are crucial in the generation of neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

“…35,36,58 Previous studies have determined that the 'inflammatory' and the 'neuropathic' component of pain in CP may not be independent but instead closely linked: The 'neuro-immune crosstalk' through pancreatic neuritis, and changes in intrapancreatic neural plasticity were all associated with the severity of pain experienced by CP patients. 8,10,33,58 In addition, recent studies support the idea that the peripheral immune system and spinal microglia are crucial in the generation of neuropathic pain. 35,37,58 The contribution of fractalkine to general neuropathic pain was shown earlier: In several experimental models of neuropathic pain, it was shown that endogenous fractalkine is released by DRG and is accompanied by the upregulation of CX3CR1 in the spinal microglia and neuropathic pain behavior.…”

Section: Discussionmentioning

confidence: 99%

“…58 Although several components of pancreatic neuropathy, including increased neural density and hypertrophy, were shown to be linked to pain sensation in CP, the role of another possible contributor, namely glia cells in CP, remains uninvestigated. In CP, increased neural and tissue fractalkine did not account for all the mechanisms of pain in CP, as changes in intrapancreatic neural plasticity were found as fractalkine-unrelated correlates of pain.…”

Section: Discussionmentioning

confidence: 99%

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Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Ceyhan

Deucker

Demir

et al. 2009

Laboratory Investigation

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The chemokine fractalkine induces migration of inflammatory cells into inflamed tissues, thereby aggravating inflammatory tissue damage and fibrosis. Furthermore, fractalkine increases neuropathic pain through glial activation, which can be diminished by blocking of its receptor, CX3CR1, through neutralizing antibodies. As chronic pancreatitis (CP) is characterized by tissue infiltration of inflammatory cells, fibrosis, pancreatic neuritis and severe pain, the roles of fractalkine and CX3CR1 were investigated in CP (n ¼ 61) and normal pancreas (NP, n ¼ 21) by QRT-PCR, western blot and immunohistochemistry analyses. Their expression correlated with the severity of pancreatic neuritis, fibrosis, intrapancreatic nerve fiber density and hypertrophy, pain, CP duration and with the amount of inflammatory cell infiltrate immuno-positive for CD45 and CD68. To investigate the influence of fractalkine on pancreatic fibrogenesis, human pancreatic stellate cells (hPSCs) were isolated from patients with CP, incubated with fractalkine and then Collagen-1 and a-smooth muscle actin (a-SMA) expressions were measured. CX3CR1, but not fractalkine, mRNA was overexpressed in CP. In contrast, the protein levels of both CX3CR1 and fractalkine were upregulated. Neuro-immunoreactivity for fractalkine and CX3CR1 was strongest in patients suffering from severe pain and pancreatic neuritis. Long-term suffering from CP was noticeably related to increased neural immunoreactivity of fractalkine. Furthermore, fractalkine and CX3CR1 mRNA overexpressions were associated with enhanced lymphocyte and macrophage infiltration. Advanced fibrosis was associated with increased fractalkine expression, whereas in vitro fractalkine had no significant impact on collagen-1 and a-SMA expressions in hPSCs. Therefore, pancreatic fractalkine expression appears to be linked to visceral pain and to the recruitment of inflammatory cells into the pancreatic tissue and nerve fibers, with subsequent pancreatic neuritis. However, pancreatic fibrogenesis is probably indirectly influenced by fractalkine. Taken together, these novel findings suggest that CX3CR1 represents a potential novel therapeutic target to reduce inflammation and modulate pain in CP.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Ceyhan

Deucker

Demir

et al. 2009

Laboratory Investigation

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“…These alterations, called PDA associated neural remodeling (PANR), result in higher nerve densities in PDA due to peripheral nerve fibers infiltration and axonogenesis (10,11). Recently, we highlighted, in a previous study, that the intra-tumoral microenvironment could be a cause of those profound alterations (12).…”

Section: Introductionmentioning

confidence: 99%

LIF Drives Neural Remodeling in Pancreatic Cancer and Offers a New Candidate Biomarker

et al. 2018

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Abstract:Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive stroma and pathogenic modifications to the peripheral nervous system that elevate metastatic capacity. In this study, we show that the IL-6-related stem cell promoting factor LIF supports PDACassociated neural remodeling (PANR). LIF was overexpressed in tumor tissue compared to healthy pancreas, but its receptors LIFR and gp130 were expressed only in intratumoral Significance:This study suggests a target to limit neural remodeling in pancreatic cancer, which contributes to poorer quality of life and heightened metastatic progression in patients.

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Diagnosis and Management of Chronic Pancreatitis

Singh

Yadav

Garg

2019

JAMA

344

195

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hronic pancreatitis (CP) is a chronic progressive disease with an annual incidence of 5 to 8 and prevalence of 42 to 73 cases per 100 000 adults in the United States. 1-3 Prevalence rates varying from 36 to 125 per 100 000 population have been reported from Japan, China, and India, of which India has the highest prevalence. 4,5 Chronic pancreatitis is characterized by fibrosis and inflammation of the pancreas in individuals with genetic, environmental, and other risk factors such as hypertriglyceridemia. Chronic pancreatitis is characterized by pancreatic atrophy, fibrosis, ductal strictures and distortion, calcifications, dysplasia, exocrine insufficiency and diabetes, and chronic pain. 6 This review summarizes current evidence regarding risk factors, pathophysiology, clinical features, diagnostic evaluation, treatment, and prognosis of CP. MethodsWe searched PubMed for relevant English-language articles published from January 1, 2000, to July 1, 2019. Search terms included chronic pancreatitis and each of the following:

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Pancreatic Neuropathy and Neuropathic Pain—A Comprehensive Pathomorphological Study of 546 Cases

Cited by 330 publications

References 39 publications

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

LIF Drives Neural Remodeling in Pancreatic Cancer and Offers a New Candidate Biomarker

Diagnosis and Management of Chronic Pancreatitis

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