Determination of the receptor selectivity of opioid agonists in the guinea‐pig ileum and mouse vas deferens by use of β‐funaltrexamine

Abstract

1 The irreversible inhibitor of μ-opioid receptor-mediated effects, β-funaltrexamine (β-FNA), was used to investigate the selectivity of various opioid agonists at μ-opioid receptors in the electrically stimulated guinea-pig ileum and mouse vas deferens preparations in vitro. 2 In the guinea-pig ileum, pretreatment with β-FNA (3 × 10⁻⁸ − 3 × 10⁻⁶ M) produced a concentration-dependent antagonism of the inhibitory effect produced by the μ-opioid receptor agonist [D-Ala², MePhe⁴, Gly(ol)⁵]enkephalin (DAGO). High concentrations of β-FNA (3 × 10⁻⁶ − 1 × 10⁻⁵ M) also antagonized the inhibitory effects of the K-opioid agonist U50488. 3 Pretreatment of guinea-pig ileum with β-FNA at 1 × 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 μ/k opioid receptor selectivity, were nalbuphine, [D-Ser², Leu⁵]enkephalinyl-Thr⁶(DSLET), morphine, DAGO and normophine. Responses to tifluadom, Mr 2034, ethylketocyclazocine, butorphanol, nalorphine, proxorphan and U50488 were not inhibited by β-FNA. 4 In the mouse vas deferens, pre-treatment with β-FNA (1 × 10⁻⁶ M) produced a similar shift in the dose-response curves for normophine as in the guinea-pig ileum. The concentration-response curves for the δ-receptor agonists [D-Ala², D-Leu⁵] enkephalin (DADLE) and DSLET were, however, also shifted, indicating that β-FNA will also block δ-opioid receptors. 5 Since β-FNA does not block k-opioid receptor-mediated effects, it can be used in the guinea-pig ileum preparation as a selective μ-receptor inhibitor. However, its lack of selectivity between μ- and δ-opioid receptors should be taken into account in many other isolated tissues and experiments in vivo.