Pharmacological Preconditioning by Corticotropin Releasing Factor (CRF) or ACTH Protects the Gastric Mucosa against Ulcerogenic Action of Indomethacin through Involvement of Glucocorticoids

Abstract

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are widely used as analgesic and anti‐inflammatory drugs. However, adverse effects, including gastrointestinal, renal, cardiovascular side effects, seriously complicate NSAIDs use. Their gastrointestinal side effects are the most known serious complications in patients taking these drugs. Previously we have shown that preconditioning stress attenuates the ulcerogenic action of indomethacin (IM) on the gastric mucosa. According our findings glucocorticoids, released in response to stressor, are gastroprotective hormones and involved in stress preconditioning protective effects. Corticotropin releasing factor (CRF), a major mediator of stress response, stimulates ACTH release through CRF receptors of subtype 1 and ACTH, in turn, stimulates glucocorticoid production. Here we verify the hypothesis that pharmacological preconditioning by CRF or ACTH can protect the gastric mucosa against ulcerogenic action of IM in rats through mechanism associated with glucocorticoids. For this, preliminary fasted (24 h) rats were administered by CRF (2.5 or 5 µg/ kg, ip) or ACTH (1U/kg, ip) 30 min before IM injection (35 mg/kg, sc). Gastric lesions were examined 4 h after IM administration. Plasma corticosterone levels were measured before and 4 h after IM injection. Since the gastrointestinal injury is accompanied by changes in somatic pain sensitivity, we also measured tail flick latencies (tail flick test) before and 4 h after IM. Both CRF and ACTH by itself caused an elevation of plasma corticosterone levels, which was accompanied by an increase of tail flick latencies (analgesic effect). IM administration resulted in the gastric erosion 4 h later. Pretreatment with CRF or ACTH reduced an area of gastric lesions caused by IM (gastroprotective effect). IM‐induced gastric injury was accompanied by an increase of tail flick latencies, which was prevented by CRF (normalization of somatic pain sensitivity). To estimate the role of glucocorticoids in CRF‐induced gastroprotection an inhibitor of corticosterone synthesis metyrapone (30 mg/kg) or CRF receptor type 1 antagonist NBI 27914 (10 mg/kg) or glucocorticoid receptor antagonist RU‐38486 (20 mg/kg) was administered before CRF. Both metyrapone and NBI 27914 injected before CRF administration caused an inhibition of CRF‐induced corticosterone response and prevented protective effect of CRF on the gastric mucosa against the IM‐induced injury. The gastroprotective effect of CRF was also eliminated by the pretreatment with RU‐38486. Thus, CRF as well as ACTH can protect the gastric mucosa against ulcerogenic action of IM. Gastroprotective action of CRF accompanied by normalization of somatic pain sensitivity is provided by mechanism associated with glucocorticoids.