Sensitization of visceral afferents to bradykinin in rat jejunum in vitro

1. We have investigated the effects of inflammatory mediators on visceral a fferent discharge and afferent responses to bradykinin (BK) in rat jejunum using a novel in vitro technique. 2. Prostaglandin E-2 (1 mu M) augmented responses to BK without affecting b asal firing, while histamine (100 mu M) and adenosine (100 mu M) activated basal discharge and enhanced BK responses. In contrast, 5-HT (100 mu M) inc reased basal discharge without influencing responses to BK. 3. Afferent discharge induced by histamine was inhibited by both H-1 (pyril amine) and H-3 (thioperamide) but not H-2 (ranitidine) receptor antagonists at 10 mu M. In contrast, sensitization to BK induced by histamine was inhi bited by ranitidine (10 mu M). 4. Afferent discharge induced by adenosine was blocked by the A(1) receptor antagonist DPCPX (10 mu M) but remained unaffected by A(2A) receptor block ade with ZM241385 (10 mu M). In contrast, sensitization of BK responses by adenosine was unaffected by both antagonists. Basal discharge and BK-induce d responses were unaffected by the A(3) receptor agonist IB-MECA (1 mu M). While involvement of A(2B) receptors is not excluded, adenosine may activat e afferent discharge through A(1) receptors, while sensitization to BK coul d involve a receptor other than A(1), A(2A) or A(3), possibly the A(2B) rec eptor. 5. Inhibition of cyclo-oxygenase with naproxen (10 mu M) prevented sensitiz ation after histamine but not adenosine. 6. Sensitization was mimicked by dibutyryl cAMP. This occurred without chan ges in basal firing and was unaffected by naproxen. 7. In conclusion, afferent discharge induced by BK is augmented by histamin e, adenosine and PGE(2), but not by 5-HT. Evidence suggests that sensitizat ion involves separate mechanisms from afferent activation. Sensitization ma y be mediated by increases in cAMP following direct activation by mediators at the nerve terminal or through indirect pathways such as the release of prostaglandins.