Fig. 3.

Model for negative modulation of antinociception by bivalent ligands. The inactive (1) and active (2) states of the μ-δ heterodimer are in equilibrium with each other. Univalent binding of the μ agonist pharmacophore of the bivalent ligand to the μ opioid receptor recognition site leads to state 3. Bridging with concomitant transformation of the δ receptor to the antagonist state negatively modulates the μ receptor (4). Displacement of the δ antagonist pharmacophore of the bridged bivalent ligand by NTI disrupts tethering of the μ and δ receptors, thereby facilitating dissociation (5). This model envisages the heterodimers to be either in an active or inactive state but not in a mixed state, except when the associated receptors are held together by the bridged bivalent ligand.