Irreversible selective blockade of kappa-opioid receptors in the guinea-pig ileum.

The irreversible non-selective opioid antagonist beta-chlornaltrexamine (beta-CNA) was used in combination with selective mu receptor protection by [D-Ala2, MePhe4, Gly(ol)5]enkephalin (DAGO) to produce an effective kappa receptor antagonism in the guinea-pig field-stimulated ileum preparation. Using a standard pre-treatment of 10(-7) M beta-CNA incubated for 15 min, DAG (10(-6)-10(-4) M) protected the response to the mu agonist normorphine while reducing the antagonism of the kappa agonist U50488 to a lesser extent. The concentration of DAGO which produced the most selective protection was 10(-5) M. This method was used to find the kappa selectivity of a series of opioid agonists. Of the compounds tested, butorphanol, dynorphin-(1-17), U50488, tifluadom, bremazocine and Mr 2034 were the most kappa-selective. The correlation with kappa agonist selectivity in vitro and effects in vitro on urine output in the rat is demonstrated.