Sensitization of visceral afferents to bradykinin in rat jejunum in vitro

1. We have investigated the effects of inflammatory mediators on visceral afferent 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 basal 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) increased basal discharge without influencing responses to BK. 3. Afferent discharge induced by histamine was inhibited by both H-1 (pyrilamine) and H-3 (thioperamide) but not H-2 (ranitidine) receptor antagonists at 10 mu M. In contrast, sensitization to BK induced by histamine was inhibited 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 blockade with ZM241385 (10 mu M). In contrast, sensitization of BK responses by adenosine was unaffected by both antagonists. Basal discharge and BK-induced 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 activate afferent discharge through A(1) receptors, while sensitization to BK could involve a receptor other than A(1), A(2A) or A(3), possibly the A(2B) receptor. 5. Inhibition of cyclo-oxygenase with naproxen (10 mu M) prevented sensitization after histamine but not adenosine. 6. Sensitization was mimicked by dibutyryl cAMP. This occurred without changes in basal firing and was unaffected by naproxen. 7. In conclusion, afferent discharge induced by BK is augmented by histamine, adenosine and PGE(2), but not by 5-HT. Evidence suggests that sensitization involves separate mechanisms from afferent activation. Sensitization may 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.