Determination of the receptor selectivity of opioid agonists in the guinea-pig ileum and mouse vas deferens by use of beta-funaltrexamine.

The irreversible inhibitor of mu-opioid receptor-mediated effects, beta-funaltrexamine (beta-FNA), was used to investigate the selectivity of various opioid agonists at mu-opioid receptors in the electrically stimulated guinea-pig ileum and mouse vas deferens preparations in vitro. In the guinea-pig ileum, pretreatment with beta-FNA (3 X 10(-8) - 3 X 10(-6)M) produced a concentration-dependent antagonism of the inhibitory effect produced by the mu-opioid receptor agonist [D-Ala2, MePhe4, Gly(ol)5]enkephalin (DAGO). High concentrations of beta-FNA (3 X 10(-6) - 1 X 10(-5)M) also antagonized the inhibitory effects of the kappa-opioid agonist U50488. Pretreatment of guinea-pig ileum with beta-FNA at 1 X 10(-6)M resulted in blockade of the effect of some opioid agonists. The compounds which showed the largest rightward shifts in their concentration-response curves, and hence the greatest mu/kappa opioid receptor selectivity, were nalbuphine, [D-Ser2, Leu5]enkephalinyl-Thr6(DSLET), morphine, DAGO and normorphine. Responses to tifluadom, Mr 2034, ethylketocyclazocine, butorphanol, nalorphine, proxorphan and U50488 were not inhibited by beta-FNA. In the mouse vas deferens, pre-treatment with beta-FNA (1 X 10(-6)M) produced a similar shift in the dose-response curves for normorphine as in the guinea-pig ileum. The concentration-response curves for the delta-receptor agonists [D-Ala2, D-Leu5] enkephalin (DADLE) and DSLET were, however, also shifted, indicating that beta-FNA will also block delta-opioid receptors. Since beta-FNA does not block kappa-opioid receptor-mediated effects, it can be used in the guinea-pig ileum preparation as a selective mu-receptor inhibitor. However, its lack of selectivity between mu- and delta-opioid receptors should be taken into account in many other isolated tissues and experiments in vivo.