Induction of endogenous tumor necrosis factor-alpha: suppression of centrally stimulated gastric motility

Gastric stasis is frequently seen in conjunction with critical infectious i llness, chronic inflammatory disorders, radiation sickness, and carcinogene sis. These conditions are associated with elevated circulating levels of th e cytokine tumor necrosis factor-alpha (TNF-alpha). The present studies exa mined the relationship between endogenously produced TNF-alpha and the cent ral neural mechanisms that augment gastric motility. Systemic lipopolysacch aride (LPS) was employed to induce TNF-alpha production in thiobutabarbital -anesthetized rats. Sixty minutes after intravenous LPS injection, gastric motility could not be stimulated by a potent centrally acting gastrokinetic stimulant, thyrotropin-releasing hormone (TRH). This failure to elicit gas tric motility via central mechanisms coincided with high circulating levels of TNF-alpha. However, intravenous injections of bethanecol, a peripherall y acting cholinergic agonist with direct gastrokinetic effects, were still able to elicit normal increases in gastric motility in the presence of TNF- alpha and LPS. Therefore, the inability to stimulate gastric motility via c entral TRH could not be attributed to the direct inhibitory effects of eith er LPS or TNF-alpha on the stomach. If the production of endogenous TNF-alp ha was suppressed via the use of urethan as the anesthetic agent, then intr avenous injections of LPS were no longer effective in suppressing gastric m otility. Thus these effects on gastric motility are not directly attributab le to LPS nor are they due to direct effects on the gastric smooth muscle. Our previous study demonstrated that microinjection of femtomole quantities of TNF-alpha in the brain stem dorsal vagal complex (DVC) can modulate gas tric motility. This central TNF-alpha effect on gastric motility was dose d ependent and required an intact vagal efferent pathway. The results from th ese two studies suggest that systemically produced TNF-alpha. may gain acce ss to the DVC to modulate gastric function.