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 microM) or drugs added to the contraluminal bathing medium. Kallidin transiently increased I(sc), an effect reduced after inhibition of neuronal conduction by 0.1 microM saxitoxin, cyclooxygenase inhibition by 10 microM indomethacin, or kinin B(2) receptor blockade by 1 microM d-arginyl-l-arginyl-l-prolyl-trans-4-hydroxy-l-prolylglycyl-3-(2-thienyl)-l-alanyl-l-seryl-d-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-l-(2alpha,3beta,7alphabeta)-octahydro-1H-indole-2-carbonyl-l-arginine (HOE-140). Its action was dependent upon extracellular Cl(-) or HCO(3)(-) ions, but was resistant to 10 microM 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 HCO(3)(-)-deficient media. Tissues pretreated with 0.1 microM [d-Pen(2,5)]-enkephalin, a selective delta-opioid agonist, displayed reduced I(sc) responses to kallidin; this effect was prevented by the delta-opioid antagonist naltrindole. At a contraluminal concentration of 1 microM, 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.