hc-030031 and Stomach-Ulcer

Activation of substance P (SP) contributes to the development and maintenance of gastric lesions, but the mechanisms underlying the release of SP and SP-mediated damage to the gastric mucosa remain unknown. Transient receptor potential ankyrin 1 (TRPA1) is expressed in SP-positive neurons in the dorsal root ganglion (DRG) and stomach of rats. We hypothesized that water immersion restraint stress (WIRS) may activate and sensitize TRPA1 in DRG neurons, subsequently inducing the release of SP from DRG and stomach cells, causing the development of acute gastric mucosal lesions (AGML).. Changes in TRPA1 and SP expression in T8-11 DRG sensory neurons and the stomach in an AGML rat model were determined by reverse transcription polymerase chain reaction, western blotting and immunohistochemistry. The SP levels of serum and gastric mucosa were measured by using an enzyme-linked immunosorbent assay (ELISA). Gastric lesions were evaluated by histopathological changes. The TRPA1 antagonist HC-030031 and TRPA1 agonists allyl isothiocyanate were used to verify effect of TRPA1 and SP on AGML.. SP and TRPA1 in the DRG and stomach were upregulated, and the serum and gastric mucosa levels of SP were increased after WIRS, which are closely associated with AGML. The release of SP was suppressed and AGML were alleviated following a selective TRPA1 antagonist HC-030031. TRPA1 agonists AITC increased release of SP and led to moderate gastric lesions. We confirmed that WIRS induced the release of SP in the DRG, stomach, serum and gastric mucosa, and in a TRPA1-dependent manner.. Upregulated SP and TRPA1 in the DRG and stomach and increased serum and gastric mucosa SP levels may contribute to stress-induced AGML. TRPA1 is a potential drug target to reduce stress-induced AGML development in patients with acute critical illnesses. This study may contribute to the discovery of drugs for AGML treatment.

Topics: Acetanilides; Animals; Disease Models, Animal; Ganglia, Spinal; Gastric Mucosa; Humans; Isothiocyanates; Male; Neurons; Purines; Rats; Rats, Wistar; Stomach Ulcer; Stress, Psychological; Substance P; TRPA1 Cation Channel

To evaluate whether non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity.. Results showed that two opioids and a GC-C agonist, morphine, asimadoline and linaclotide, respectively, the TRP antagonists, AMG9810 and HC-030031 and the sodium channel blocker, carbamazepine, elicited a dose- and/or time-dependent attenuation of referred visceral hypersensitivity, while the ASIC blocker, amiloride, was ineffective at all doses tested.. Together, these findings implicate opioid receptors, GC-C, and sodium and TRP channel activation as possible mechanisms associated with visceral hypersensitivity. More importantly, these findings also validate NSAID-induced gastropathy as a sensitive and clinically predictive mouse model suitable for assessing novel molecules with potential pain-attenuating properties.

Topics: Acetanilides; Acid Sensing Ion Channel Blockers; Acid Sensing Ion Channels; Acrylamides; Amiloride; Analgesics; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Hyperalgesia; Male; Mice; Morphine; Pain Measurement; Purines; Random Allocation; Receptors, Atrial Natriuretic Factor; Receptors, Opioid; Stomach Ulcer; Transient Receptor Potential Channels; Visceral Pain