Opioid regulation of mucosal ion transport in the mouse isolated jejunum

Opioid control of mucosal ion transport was examined in intact, full thickness preparations of mouse jejunum in vitro, using standard Ussing chamber techniques. DPDPE and DAMGO were used as selective agonists for delta and mu subtypes of opioid receptors, respectively, whereas U50,488H [trans-(±)-3,4-di-chloro-N-Me-N-[2-(1-pyrrolidinyl]-benzene-acedamide -methanesulfonate] and U69,593 [(5α,7α,8β)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxa-spiro-(4,5)-de c-8-yl]-benzeaneacetamide} were used as selective agonists at the kappa-opioid receptor. When added to the serosal medium of intact tissues, DPDPE, DAMGO, U50,488H and morphine, but not U69,593, produced a concentration-dependent reduction of basal transmural potential difference and short-circuit current (I(sc)), and an increase in tissue conductance. DPDPE was 41-, 341- and 476-fold more potent than DAMGO, U50,488H and morphine, respectively, in producing these effects, although all these compounds were equiefficacious. DPDPE, but not DAMGO, U50,488H or U69,593, caused a similar effect on basal I(sc) when added to the mucosal medium. Naloxone produced a rightward shift in the concentration-effect curve for DAMGO and DPDPE, yielding distinct K(e) values for naloxone of 9.7 ± 0.5 and 42.9 ± 7.9 nM, respectively. In contrast, ICI 174,864, a delta-selective antagonist, blocked the I(sc) response induced by DPDPE but not DAMGO. The I(sc) response of U50,488H, however, was neither blocked nor reversed by naloxone or ICI 174,864, nor blocked by norbinaltorphimine, suggesting that the response was not mediated via opioid receptors. Ion flux studies revealed that DPDPE and DAMGO increased the mucosal to serosal fluxes of Na⁺ and Cl^-, suggesting a prominent proabsorptive effect; in addition, DPDPE, but not DAMGO, significantly reduced serosal to mucosal chloride flux. The I(sc) responses of DPDPE and DAMGO were not exhibited in intact tissues that were pretreated with tetrodotoxin or chlorisondamine, a ganglionic blocker, or in mucosal preparations that were physically stripped of the enteric ganglia and muscularis externa. When examined for their antisecretory potential, DAMGO and DPDPE failed to reduce the increase of I(sc) induced by theophylline, prostaglandin E₂ or 1,1-dimethyl-4-phenylpiperazinium. In comparison, norepinephrine attenuated the increase of I(sc) induced by all three secretagogues; this attenuation was reversed by yohimbine, an alpha-2 adrenoceptor antagonist. These findings support the involvement of delta and mu receptors in the neuroregulation of mucosal ion transport in the mouse jejunum. Furthermore, activation of these opioid mechanisms elicit proabsorptive changes in basal NaCl transport, without directly affecting intestinal hypersecretion induced by various secretory stimuli.