Kinin-induced anion-dependent secretion in porcine ileum: Characterization and involvement of opioid- and cannabinoid-sensitive enteric neural circuits

The intestinal secretory actions of the proinflammatory peptide kallidin (lysyl-bradykinin) are mediated partially by enteric neurons. We hypothesized that kallidin produces neurogenic anion secretion through opioid- and cannabinoid-sensitive enteric neural pathways. Changes in short-circuit current (I_sc) across sheets of porcine ileal mucosa-submucosa mounted in Ussing chambers were measured in response to kallidin (1 μM) or drugs added to the contraluminal bathing medium. Kallidin transiently increased I_sc, an effect reduced after inhibition of neuronal conduction by 0.1 μM saxitoxin, cyclooxygenase inhibition by 10 μM indomethacin, or kinin B₂ receptor blockade by 1 μM D-arginyl-L-arginyl-L-prolyltrans-4-hydroxy-L-prolylglycyl-3-(2-thienyl)- L-alanyl-L-seryl-D-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-L-(2α, 3β,7αβ)-octahydro-1H-indole-2-carbonyl-L-arginine (HOE-140). Its action was dependent upon extracellular Cl^- or HCO₃^- ions, but was resistant to 10 μM bumetanide or 0.3 mM 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid, and seemed to involve luminal alkalinization as measured by pH-stat titration. Kallidin-induced I_sc elevations were sensitive to saxitoxin in tissues bathed in Cl^--, but not HCO₃^--deficient media. Tissues pretreated with 0.1 μM [D-Pen^2,5]-enkephalin, a selective δ-opioid agonist, displayed reduced I_sc responses to kallidin; this effect was prevented by the δ-opioid antagonist naltrindole. At a contraluminal concentration of 1 μM, the cannabinoid receptor agonist (6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6, 6-dimethyl-6H-dibenzo-[b,d]pyran-9-methanol (HU-210) also attenuated responses to kallidin. Proinflammatory kinins seem to stimulate neurogenic anion secretion in porcine ileum by activating enteric neural circuits expressing inhibitory opioid and possibly cannabinoid receptors.