Toward an animal model of chronic pancreatitis

Rutishauser, Sigrid C. B.; Ali, A. E.; Jeffrey, I; Hunt, Linda; Braganza, Joan M.

doi:10.1007/bf02785885

Cited by 9 publications

(1 citation statement)

References 18 publications

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“…LY3038404 HCl's tissue protective effect is most likely related to key roles of CB2 receptor activators as antioxidants and inhibitors of cell proliferation shown by others [32]. This tissue protective effect is supported by the preponderance of studies to date indicating that the CB2 cannabinoid receptor is linked to cytochrome P450 mono-oxygenases [33] and is a modulator of the majority of immune functional responses [12,14,34]. Michler et al [24] demonstrated the importance of CB2 activation in protective modulation involving MAPK p38 and MK2 dependent pathways in an acute pancreatitis model.…”

Section: Resultsmentioning

confidence: 95%

Cannabinoid Receptor 2 Agonist Attenuates Pain Related Behavior in Rats with Chronic Alcohol/High Fat Diet Induced Pancreatitis

et al. 2014

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BackgroundChronic Pancreatitis (CP) is a complex and multifactorial syndrome. Many contributing factors result in development of dysfunctional pain in a significant number of patients. Drugs developed to treat a variety of pain states fall short of providing effective analgesia for patients with chronic pancreatitis, often providing minimal to partial pain relief over time with significant side effects. Recently, availability of selective pharmacological tools has enabled great advances in our knowledge of the role of the cannabinoid receptors in pathophysiology. In particular, cannabinoid receptor 2 (CB2) has emerged as an attractive target for management of chronic pain, as demonstrated in several studies with inflammatory and neuropathic preclinical pain models. In this study, the analgesic efficacy of a novel, highly selective CB2 receptor agonist, LY3038404 HCl, is investigated in a chronic pancreatitis pain model, induced with an alcohol/high fat (AHF) diet.ResultsRats fed the AHF diet developed visceral pain-like behaviors detectable by week 3 and reached a maximum at week 5 that persists as long as the diet is maintained. Rats with AHF induced chronic pancreatitis were treated with LY3038404 HCl (10 mg/kg, orally, twice a day for 9 days). The treated animals demonstrated significantly alleviated pain related behaviors after 3 days of dosing, including increased paw withdrawal thresholds (PWT), prolonged abdominal withdrawal latencies (ABWL), and decreased nocifensive responses to noxious 44°C hotplate stimuli. Terminal histological analysis of pancreatic tissue sections from the AHF chronic pancreatitis animals demonstrated extensive injury, including a global pancreatic gland degeneration (cellular atrophy), vacuolization (fat deposition), and fibrosis. After the LY3038404 HCl treatment, pancreatic tissue was significantly protected from severe damage and fibrosis. LY3038404 HCl affected neither open field exploratory behaviors nor dark/light box preferences as measures of higher brain and motor functions.ConclusionLY3038404 HCl, a potent CB2 receptor agonist, possesses tissue protective and analgesic properties without effects on higher brain function. Thus, activation of CB2 receptors is suggested as a potential therapeutic target for visceral inflammation and pain management.

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Section: Resultsmentioning

confidence: 95%

Cannabinoid Receptor 2 Agonist Attenuates Pain Related Behavior in Rats with Chronic Alcohol/High Fat Diet Induced Pancreatitis

et al. 2014

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Toxicology of the Exocrine Pancreas

Foster¹

2009

General, Applied and Systems Toxicology

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The exocrine pancreas is not a common target organ for toxic drugs and chemicals. It is however the fifth most common human cancer in the western world, and acute and chronic pancreatitis, through various identifiable and unidentified causes, is a common disease in both the developed and developing countries of the world. Both inflammatory disease and cancer of the pancreas is correlated to lifestyle with poor diet and habits, such as moderate to high alcohol intake and smoking, having positive correlations to developing the disease. The chapter describes the functional anatomy of the organ together with its biochemistry that determines toxicity, in particular the role of oxidant damage in the development of cell and tissue damage is thought to be important. The consequences of toxic damage to the acinar cells are severe and primarily result from the auto‐activation and hence autodigestion of the tissue by the digestive enzymes normally contained within the exocrine cells, a cascade of apoptosis/necrosis and fibrosis with the ultimate collapse of the organ, subsequent shock, multi‐organ collapse and death. The organ has complex molecular mechanisms to prevent premature activation of the digestive enzymes and also has defence mechanisms present to neutralise any premature enzyme activation but these can be rendered ineffectual by factors such as alcohol abuse and a poor diet. Chemical exposure, through both occupational and consumer product usage, has been associated with the development of both pancreatic neoplastic and non‐neoplastic disease but the relationship between exposure and disease has never developed further than a simple association and it is likely that the development of pancreatic disease is a multi‐faceted combination of inter‐related events, none of which in isolation can induce disease. The pancreas has its own array of phase 1 and 2 metabolic enzyme systems and the role of pancreatic drug and chemical activation and detoxification in inducing toxicity is discussed together with the possible secondary effects of hepatic drug/chemical activation and detoxification. Finally the role of animal models of pancreatic disease is discussed in terms of their contribution to understanding the aetiology of the human conditions and the possible use of therapeutic intervention in treating the disease.

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