Effects of neuropeptide Y, peptide YY and sigma ligands on ion transport in mouse jejunum

The effects of putative σ ligands and two neuropeptides on intestinal ion transport were evaluated in isolated sheets of whole mouse jejunum mounted in Ussing flux chambers. Serosal administration of neuropeptide Y (NPY), peptide YY (PYY), (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1- ylamine hydrochloride (JO 1784), di(ortho-tolyl) guanidine (DTG) and (+)- or (-)-N-allyl-normetazocine (NANM) produced concentration-related decreases in short-circuit current (I(sc)) without changes in tissue conductance. Although NPY and PYY were active in nanomolar concentrations, JO 1784, DTG and (+)- and (-)-NANM were active in micromolar concentrations; the rank order of potency in inhibiting I(sc) was PYY > NPY >> JO 1784 = (-)-N- cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride > DTG > (+)-NANM = (-)-NANM. Serosal application of tetrodotoxin effectively blocked the decrease in I(sc) associated with all of the ligands tested. The activity of the serosally applied ligands was blocked by prior application of chlorisondamine, a ganglionic blocker. The effects of JO 1784 and NPY were evaluated using antagonists of several receptor types. Although application of serosal haloperidol had no effect alone up to concentrations of 1 μM, this compound produced a rightward displacement in both the NPY and JO 1784 concentration-effect curves. In contrast, sulpiride, SCH-23390, naloxone, yohimbine and prazosin failed to antagonize the effects of NPY or JO 1784. Application of NPY and JO 1784 on the mucosal side of intact jejunum showed that both compounds maintained activity, though the potency of each was considerably reduced compared to serosal administration. Finally, the activity of both NPY and JO 1784 was greatly reduced in a jejunal preparation physically stripped of the enteric ganglia and muscularis externa (i.e., mucosal preparation). The data indicate that putative σ ligands and NPY and PYY produce a concentration-related and haloperidol- sensitive reduction in I(sc), which is mediated via actions on nerves, and that these effects are mediated mainly through preganglionic sites. Furthermore, the insensitivity of the responses of JO 1784 and NPY to antagonists at opioid, dopaminergic or adrenergic receptors suggests that the effects of NPY and JO 1784 may be associated with a putative σ site. These data suggest that a novel application of potential therapeutic interest will be the development of σ ligands for the investigation and treatment of gastrointestinal disorders.