Opiate receptor binding-effect relationship: sufentanil and etorphine produce analgesia at the mu-site with low fractional receptor occupancy.

The analgesic activity of the opiate agonists etorphine and sufentanil and the antagonistic effects of diprenorphine and naloxone have been related to the occupancy of 3 classes of opiate binding sites previously defined in vivo in order to establish their pharmacological significance. Sufentanil binds specifically in vivo to the first type of site (site 1), exhibiting approximately 1100-fold selectivity over site 2, whereas etorphine displays approximately 20-fold selectivity for site 1 over site 2. Neither agonist has a measurable affinity to the third type of binding site. The binding data suggest that site 1 is analogous to the mu site previously identified in vitro. Both agonists produce analgesia in the rat tail flick test at the same low fractional occupancy of site 1 (approximately 2% at the ED50) while they display much lower and quite different occupancies at site 2. Both of the opiate antagonists naloxone and diprenorphine reduce the potency of sufentanil and etorphine by a factor of 2 at 50% occupancy of site 1 alone. These results provide strong evidence that these 4 drugs exert their effects by interaction with site 1 (mu sites) which therefore may be regarded as the receptor responsible for analgesic action in this test. The assumption of a direct relationship between antagonistic effect and fractional occupancy appears to be valid for naloxone and diprenorphine at site 1, while the agonists exert their action at a very low fractional occupancy implying a non-linear binding-effect process.