ceruletide and Abdominal-Pain

Agents that modulate the activity of high-voltage gated calcium channels (HVCCs) exhibit experimentally and clinically significant effect by relieving visceral pain. Among these agents, the toxins Phα1β and ω-conotoxin MVIIA effectively reduce chronic pain in rodent models. The molecular mechanisms underlying the chronic pain associated with acute pancreatitis (AP) are poorly understood. Hypercalcemia is a risk factor; the role of cytosolic calcium is considered to be a modulator of pancreatitis. Blockade of Ca

Topics: Abdominal Pain; Analgesics; Animals; Anti-Inflammatory Agents; Behavior, Animal; Calcium Channel Blockers; Calcium Channels; Calcium Signaling; Ceruletide; Disease Models, Animal; Exploratory Behavior; Hyperalgesia; Inflammation Mediators; Male; Neuropeptides; omega-Conotoxins; Pain Threshold; Pancreas; Pancreatitis; Rats, Wistar; Spider Venoms; Spinal Cord

Animal models are essential to understand the pathogenesis of acute pancreatitis (AP) and to develop new therapeutic strategies. Although it has been shown that cerulein-induced AP is associated with pain in experimental animals, most experiments are carried out without any pain-relieving treatment because researchers are apprehensive of an interference of the analgetic agent with AP-associated inflammation. In light of the growing ethical concerns and the legal tightening regarding animal welfare during experiments, this attitude should be changed.. Acute pancreatitis was induced by cerulein in the C57BL/6J and FVB/N mouse inbred strains. One group received vehicle only, and the other was treated with metamizol as analgetic agent. Pain sensation and parameters of AP were analyzed as well as the effect of metamizol in the pancreas and its actions in the brain.. We report that oral administration of metamizol protects cerulein-treated mice from abdominal pain without influencing the clinical and histopathological course of the disease. In addition, it could be shown that metamizol reduces the central pain response.. This study reveals that oral administered metamizol has no influence on the cerulein-induced AP and can be given as an analgesic to increase animal welfare in experiments with induced AP.

Topics: Abdominal Pain; Acute Disease; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Brain; Ceruletide; Cyclooxygenase 2; Dinoprostone; Dipyrone; Disease Models, Animal; Humans; Hypothalamus; Male; Mice, Inbred C57BL; Mice, Inbred Strains; Pancreatitis; Proto-Oncogene Proteins c-fos; Thalamus

Kaempferol (KF) is the most abundant polyphenol in tea, fruits, vegetables, and beans. However, little is known about its in vivo anti-inflammatory efficacy and mechanisms of action. To study these, several acute mouse inflammatory and nociceptive models, including gastritis, pancreatitis, and abdominal pain were employed. Kaempferol was shown to attenuate the expansion of inflammatory lesions seen in ethanol (EtOH)/HCl- and aspirin-induced gastritis, LPS/caerulein (CA) triggered pancreatitis, and acetic acid-induced writhing.

Topics: Abdominal Pain; Acetic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Ceruletide; Disease Models, Animal; Gastritis; Kaempferols; Mice; Nociception; Pancreatitis

Acute pancreatitis is a life-threatening inflammatory disease characterized by abdominal pain of unknown etiology. Trypsin, a key mediator of pancreatitis, causes inflammation and pain by activating protease-activated receptor 2 (PAR(2)), but the isoforms of trypsin that cause pancreatitis and pancreatic pain are unknown. We hypothesized that human trypsin IV and rat P23, which activate PAR(2) and are resistant to pancreatic trypsin inhibitors, contribute to pancreatic inflammation and pain. Injections of a subinflammatory dose of exogenous trypsin increased c-Fos immunoreactivity, indicative of spinal nociceptive activation, but did not cause inflammation, as assessed by measuring serum amylase and myeloperoxidase activity and by histology. The same dose of trypsin IV and P23 increased some inflammatory end points and caused a more robust effect on nociception, which was blocked by melagatran, a trypsin inhibitor that also inhibits polypeptide-resistant trypsin isoforms. To determine the contribution of endogenous activation of trypsin and its minor isoforms, recombinant enterokinase (ENK), which activates trypsins in the duodenum, was administered into the pancreas. Intraductal ENK caused nociception and inflammation that were diminished by polypeptide inhibitors, including soybean trypsin inhibitor and a specific trypsin inhibitor (type I-P), and by melagatran. Finally, the secretagogue cerulein induced pancreatic nociceptive activation and nocifensive behavior that were reversed by melagatran. Thus trypsin and its minor isoforms mediate pancreatic pain and inflammation. In particular, the inhibitor-resistant isoforms trypsin IV and P23 may be important in mediating prolonged pancreatic inflammatory pain in pancreatitis. Our results suggest that inhibitors of these isoforms could be novel therapies for pancreatitis pain.

Topics: Abdominal Pain; Acute Disease; Amylases; Analgesics; Animals; Azetidines; Benzylamines; Ceruletide; Disease Models, Animal; Enteropeptidase; Enzyme Activation; Humans; Kinetics; Male; Pain Measurement; Pancreas; Pancreatitis; Peroxidase; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptor, PAR-2; Recombinant Proteins; Signal Transduction; Soybean Proteins; Spinal Cord; Trypsin; Trypsin Inhibitors

Camostat mesilate, an orally available proteinase inhibitor, is clinically used for treatment of pancreatitis. Given recent evidence that pancreatic proteinases including trypsin and/or proteinase-activated receptor-2 (PAR2) might be involved in pancreatic pain, we examined if camostat mesilate could suppress spinal Fos expression, a marker for neuronal activation, following specific application of trypsin to the pancreas, and pancreatitis-related referred allodynia. Trypsin, administered into the pancreatic duct, caused delayed expression of Fos proteins in the superficial layer of the bilateral T8 and T9 spinal dorsal horns in rats. The trypsin-induced spinal Fos expression was completely abolished by oral pre-administration of camostat mesilate at 300 mg/kg. After hourly repeated (6 times in total) administration of caerulein, mice showed typical symptoms of pancreatitis, accompanied by mechanical allodynia in the upper abdomen (i.e., referred hyperalgesia/allodynia), as assessed by use of von Frey filaments. Camostat mesilate at 100-300 mg/kg, given orally twice before the 1st and 4th doses of caerulein, abolished the pancreatitis-related abdominal allodynia, while it partially prevented the inflammatory signs. The same doses of camostat mesilate, when administered once after the final dose of caerulein, also revealed significant anti-allodynic effect. These data suggest that camostat mesilate prevents and/or depresses pancreatitis-induced pain and/or referred hyperalgesia/allodynia, in which proteinases including trypsin would play a critical role.

Topics: Abdominal Pain; Animals; Ceruletide; Dose-Response Relationship, Drug; Esters; Gabexate; Guanidines; Male; Pain, Referred; Pancreatitis; Physical Stimulation; Posterior Horn Cells; Protease Inhibitors; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Trypsin

1 Proteinase-activated receptor-2 (PAR2), a receptor activated by trypsin and tryptase, is abundantly expressed in the gastrointestinal tract including the C-fiber terminal, and might play a role in processing of visceral pain. In the present study, we examined and characterized the roles of PAR2 in pancreatitis-related abdominal hyperalgesia/allodynia in mice. 2 Caerulein, administered i.p. once, caused a small increase in abdominal sensitivity to stimulation with von Frey hairs, without causing pancreatitis, in PAR2-knockout (KO) mice, but not wild-type (WT) mice. 3 Caerulein, given hourly six times in total, caused more profound abdominal hyperalgesia/allodynia in PAR2-KO mice, as compared with WT mice, although no significant differences were detected in the severity of pancreatitis between the KO and WT animals. 4 The PAR2-activating peptide, 2-furoyl-LIGRL-NH(2), coadministered repeatedly with caerulein six times in total, abolished the caerulein-evoked abdominal hyperalgesia/allodynia in WT, but not PAR2-KO, mice. Repeated doses of 2-furoyl-LIGRL-NH(2) moderately attenuated the severity of caerulein-induced pancreatitis in WT animals. 5 Our data from experiments using PAR2-KO mice provide evidence that PAR2 functions to attenuate pancreatitis-related abdominal hyperalgesia/allodynia without affecting pancreatitis itself, although the PAR2AP applied exogenously is not only antinociceptive but also anti-inflammatory.

Topics: Abdominal Pain; Analgesics; Animals; Ceruletide; Female; Hyperalgesia; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligopeptides; Pain Measurement; Pain Threshold; Pancreatitis; Receptor, PAR-2; Touch