Recent clinical studies have suggested a risk of adverse gastric reactions from the concomitant use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) with nonsteroidal anti-inflammatory drugs (NSAIDs). We examined the adverse effects of SSRIs on antral lesions produced by indomethacin in rats. Rats fasted for 24 h were refed for 1 h, then administered indomethacin (30 mg/kg) s.c. 1 h after the refeeding, and killed 6 h later. Paroxetine (1~10 mg/kg) was given p.o. 30 min before indomethacin. Indomethacin caused antral lesions in re-fed rats. Paroxetine dose-dependently aggravated these lesions, despite provoking no damage by itself. Similar results were obtained when other NSAIDs such as diclofenac, flurbiprofen, and loxoprofen were co-administered with paroxetine or when indomethacin was co-administered with other antidepressants such as fluvoxamine and milnacipran, but not imipramine or maprotiline. Exogenous 5-HT also worsened the indomethacin-induced antral damage, while the aggravating effect of paroxetine was attenuated by ondansetron, a selective 5-HT3 antagonist, but not antagonists for other 5-HT receptor subtypes. Indomethacin plus paroxetine had no effect on gastric secretion but significantly decreased mucosal superoxide dismutase (SOD) activity as well as glutathione content. The antral damage induced by indomethacin plus paroxetine was significantly prevented by antisecretory (acid or pepsin) agents and mucosal protective agents as well as SOD and allopurinol. These results suggest that SSRIs aggravate NSAID-induced antral lesions, probably via the activation of 5HT3 receptors, and the mechanism of aggravation may involve the corrosive action of acid/pepsin as well as an impaired anti-oxidative system.
- gastric ulcer
- non-steroidal anti-inflammatory drugs (NSAIDs)
- oxidative stress
- superoxide dismutases (SOD)
- Received April 24, 2011.
- Revision received June 21, 2011.
- Accepted June 21, 2011.
- The American Society for Pharmacology and Experimental Therapeutics