The role of peripheral serotonin and norepinephrine in the gastroprotective effect against stress of duloxetine

Duloxetine has been shown to produce gastroprotective effect against gastric ulcer induced by water immersion restraint stress (WIRS) via modulation of NADPH oxidases in the gastric mucosa and neurometabolites of central nucleus of amygdala. However, the underlying mechanism based on the basic pharmacological function of duloxetine-regulation on serotonin (5-HT) and norepinephrine (NE) remains unclear. Here, we found that 5-HT level in platelet-poor plasma (PPP) was decreased but NE level in plasma was increased in rats exposed to WIRS, while pretreatment with duloxetine increased 5-HT in PPP dose-dependently and decreased NE in plasma of rats after WIRS. We further showed that depletion of 5-HT by 4-chloro-DL-phenylalanine (PCPA) aggravated gastric mucosa damage and supplement of 5-HT alleviated gastric ulcers induced by WIRS. Blockade of NE receptors also mitigated the stress gastric ulcers. Using adrenalectomy and chemical blocking, we identified that it was NE from adrenal medulla rather than sympathetic nerve that was more critical in the gastroprotection of duloxetine, and intriguingly, glucocorticoid did not make a difference in WIRS-provoked gastric ulcers as a classic stress hormone. Together, our work demonstrated prophylactic protection of duloxetine from the stress gastric ulcer depended on enhancing peripheral 5-HT content and reducing NE from adrenal medulla, which provided insight into treatments of WIRS-induced gastric ulcer.