Calcium channels blockers toxins attenuate abdominal hyperalgesia and inflammatory response associated with the cerulein-induced acute pancreatitis in rats

• Published in: European journal of pharmacology 2021-01, Vol.891, p.173672-173672, Article 173672
• Main Authors: Ricardo Carvalho, Vanice Paula, Figueira da Silva, Juliana, Buzelin, Marcelo Araújo, Antônio da Silva Júnior, Cláudio, Carvalho dos Santos, Duana, Montijo Diniz, Danuza, Binda, Nancy Scardua, Borges, Márcia Helena, Senna Guimarães, André Luiz, Rita Pereira, Elizete Maria, Gomez, Marcus Vinicius
• Format: Article
• Language: English
• Subjects: Abdominal Pain - etiology; Abdominal Pain - metabolism; Abdominal Pain - physiopathology; Abdominal Pain - prevention & control; Acute pancreatitis; Analgesics - pharmacology; Animals; Anti-Inflammatory Agents - pharmacology; Behavior, Animal - drug effects; Calcium Channel Blockers - pharmacology; Calcium Channels - drug effects; Calcium Channels - metabolism; Calcium Signaling - drug effects; Cerulein; Ceruletide; CTK -01512-2; Disease Models, Animal; Exploratory Behavior - drug effects; Hyperalgesia; Hyperalgesia - etiology; Hyperalgesia - metabolism; Hyperalgesia - physiopathology; Hyperalgesia - prevention & control; Inflammation Mediators - metabolism; Male; Neuropeptides - pharmacology; omega-Conotoxins - pharmacology; Pain Threshold - drug effects; Pancreas - drug effects; Pancreas - metabolism; Pancreatitis - chemically induced; Pancreatitis - metabolism; Pancreatitis - physiopathology; Pancreatitis - prevention & control; Phα1β; Rats; Rats, Wistar; Spider Venoms - pharmacology; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord - physiopathology; ω-Conotoxin MVIIA
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2020.173672

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 Ca2+ signals may be useful as a prophylactic treatment of pancreatitis. We explored the pathophysiological roles of three peptide toxins: Phα1β and its recombinant form CTK 01512-2—blockers of TRPA1 receptor and HVCCs and ω-conotoxin MVIIA, a specific blocker of N-type calcium channels in cerulein-induced AP. Cerulein injection elicits AP in rats, evidenced by an increase in hyperalgesic pain, inflammatory infiltration, amylase and lipase secretion, and reactive oxygen species, TNF-α, and p65 NF-κB levels. These effects of cerulein-induced AP were abolished by Phα1β and its recombinant form CTK 01512-2, whereas ω-conotoxin MVIIA had no effect on the induced increase in pancreatic enzyme secretion. Our results demonstrate that Phα1β and CTK 01512-2 toxins—antagonists of HVCCs and TRPA1 receptor presented an effective response profile, in the control of nociception and inflammatory process in the AP model in rats, without causing changes in spontaneous locomotion of the rats.