Nonsteroidal anti‐inflammatory drugs (NSAIDs) such as indomethacin (IM) are commonly used; however their use is complicated by the side effects on the gastrointestinal tract. Gastrointestinal injury triggers the changes in visceral as well as somatic pain sensitivity in rats. Here we studied the effect of acute and chronic stress on somatic pain sensitivity under circumstances of IM‐induced gastric injury in conscious rats. Gastric erosion was caused by a single IM injection (35 mg/kg, sc) in preliminary (24 h) fasted rats. Somatic pain sensitivity was assessed by tail flick test. The animals were habituated for tail flick test for 7 days and examined for baseline tail flick latency on day 8. Then, animals were exposed to IM administration with acute or chronic stress or without stress. Cold‐restraint stress at 10 °C for 30 min and keeping at room temperature 1h before IM was used as acute stress. For chronic stress the rats were subjected to unpredictable stress of various modalities for 14 days daily and injected by IM on day 15. Tail flick latencies were measured after stress (before IM) and 4 h after IM administration. Gastric mucosa injury, plasma corticosterone levels, blood pressure, heart rate, adrenal and thymus weight were also measured. IM caused gastric injury 4h after its administration. Acute or chronic stress by itself did not influence gastric mucosa, but its action manifested under circumstances of IM‐induced gastric injury. Acute stress attenuated the ulcerogenic effect of IM on gastric mucosa, but chronic stress potentiated it. The formation of gastric erosion was accompanied by an increase in tail flick latencies (somatic hypoalgesia). We did not observe any changes in tail flick latencies 1h after cold‐restaint stress. However, acute stress prevented somatic hypoalgesia induced by gastric injury. In contrast to acute stress, chronic stress attenuated tail flick latencies before IM administration, but did not affect somatic hypoalgesia. The data obtained suggests that chronic stress aggravates the ulcerogenic action of IM on gastric mucosa that is accompanied by an increase in somatic pain sensitivity, whereas acute stress plays the protective role in the maintenance of integrity of gastric mucosa and preventing of pain abnormalities induced by pathological process in stomach. Support or Funding Information The study was supported by grant of Russian Science Foundation (RSF) №14‐15‐00790.
In the present study we investigated whether CRF injected into the brain or the periphery induces protection against indomethacin‐caused gastric injury and the role of glucocorticoids, the CRF receptor types 1 and 2 (CRF1 and CRF2 receptors) in the protection. Gastric injury was caused by indomethacin (35 mg/kg, subcutaneously) in preliminary fasted rats and CRF was injected 30 min before indomethacin administration. The participation of glucocorticoids was studied by inhibitor of glucocorticoids’ synthesis metyrapone, and glucocorticoid receptor antagonist RU‐38486. The role of the CRF1 and CRF2 receptors was investigated by the nonselective CRF1/CRF2 receptor antagonist astressin, the selective CRF1 receptor antagonist NBI 27914, and the selective CRF2 receptor antagonist astressin2‐B. Intracerebroventricular or intraperitoneal injection of CRF at the doses, which markedly increased plasma corticosterone levels, significantly suppressed the occurrence of gastric erosion induced by indomethacin. The protective effect of CRF on the gastric mucosa against indomethacin‐produced injury was significatly attenuated by metyrapone and RU‐38486 as well as by astressin, NBI 27914 and also astressin2‐B. The results suggest that CRF injected into the brain or the periphery may induce protection against indomethacin‐caused gastric injury through glucocorticoids, CRF1 and CRF2 receptors. Grant Funding Source : Supported by grants from RFBR N13‐04‐01680‐a and Programs of Presidium RAS 7P
