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 E2 (1 microM) augmented responses to BK without affecting basal firing, while histamine (100 microM) and adenosine (100 microM) activated basal discharge and enhanced BK responses. In contrast, 5-HT (100 microM) increased basal discharge without influencing responses to BK. 3. Afferent discharge induced by histamine was inhibited by both H1 (pyrilamine) and H3 (thioperamide) but not H2 (ranitidine) receptor antagonists at 10 microM. In contrast, sensitization to BK induced by histamine was inhibited by ranitidine (10 microM). 4. Afferent discharge induced by adenosine was blocked by the A1 receptor antagonist DPCPX (10 microM) but remained unaffected by A2A receptor blockade with ZM241385 (10 microM). In contrast, sensitization of BK responses by adenosine was unaffected by both antagonists. Basal discharge and BK-induced responses were unaffected by the A3 receptor agonist IB-MECA (1 microM). While involvement of A2B receptors is not excluded, adenosine may activate afferent discharge through A1 receptors, while sensitization to BK could involve a receptor other than A1, A2A or A3, possibly the A2B receptor. 5. Inhibition of cyclo-oxygenase with naproxen (10 microM) 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 PGE2, 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.
Brunsden
A M
AM
Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield S10 2TN, UK. a.brunsden@sheffield.ac.uk
Grundy
D
D
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000502:physiology; D006632:Histamine / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007583:Jejunum / Q000294:innervation*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009288:Naproxen / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000502:physiology; D013268:Stimulation, Chemical; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D006633:Histamine Antagonists; D006635:Histamine H2 Antagonists; D010880:Piperidines; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; D012701:Serotonin; D009288:Naproxen; D003994:Bucladesine; D006632:Histamine; D011899:Ranitidine; C051360:1,3-dipropyl-8-cyclopentylxanthine; C052075:thioperamide; D000241:Adenosine; D015232:Dinoprostone; D001920:Bradykinin