Pharmacological studies on the "orphan" opioid receptor in central and peripheral sites

We have exploited the availability of the "orphan" opioid receptor (referred to here as ORL1) in its "natural state" to investigate the effect of nociceptin (orphanin FQ), the endogenous agonist for the ORL1 receptor in the brain, vas deferens, and myenteric plexus of the small intestine. Nociceptin was a potent agonist in electrically stimulated preparations of vasa deferentia (rat and rabbit) and myenteric plexus (guinea-pig) (IC50 ranging from 18 to 31 nM) and susceptible to enzymic cleavage as addition of a cocktail of peptidase inhibitors to the organ bath produced a leftward shift in concentration-response curves (IC50 ranging from 2.1 to 4.9 nM). In radioligand binding experiments using brain membranes from rat, rabbit, and guinea-pig, [3H]nociceptin bound a single population of binding sites with high affinity (KD values ranging from 0.049 to 0.124 nM) and capacity (Bmax ranging from 143 to 254 fmol.mg-1 protein). However, the response to nociceptin in functional studies and in radioligand binding inhibitory assays was resistant to antagonism/displacement by naloxone and a range of other opioid receptor antagonists, thus displaying a very different pharmacological profile from that of the "classical" opioids. Therefore, we conclude that the effect of nociceptin in these studies is not via an action at mu, delta, or kappa opioid receptors but rather at an orphan opioid receptor, ORL1.