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

Abstract

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. 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. 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. 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. 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. 1985 British Pharmacological Society