Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores

Treatment of pain with opioids is limited by their potential abuse liability. In an effort to develop analgesics without this side effect, a series of bivalent ligands containing a mu-opioid receptor agonist pharmacophore connected to a delta-opioid receptor antagonist pharmacophore through variable-length spacers (16–21 atoms) was synthesized. Members of this series [mu-opioid receptor (M)-delta-opioid receptor (D)-agonist (A)-antagonists (N): MDANs] are antinociceptive in the tail flick assay, but antinociceptive tolerance and physical dependence do not develop to ligands having spacers with 19–21 atoms. The current studies compared the rewarding properties of three bivalent ligands (MDAN-16, -19 and -21) and a mu-opioid receptor agonist (MA-19) to those of morphine in the conditioned place preference assay in mice after i.v. administration. Place preference developed to morphine and to MA-19, but not to the MDANs. The responses to MDAN-16 were highly variable, although place preference of borderline significance appeared to develop. Reinstatement was also evaluated after extinguishing morphine conditioned place preference; morphine and MA-19, but not the MDANs, reinstated morphine conditioned place preference. Taken together, these results suggest that the bivalents are less rewarding compared to morphine in opioid-naïve mice and do not induce reinstatement in previously morphine-preferring mice. The lack of a conditioned place preference response for MDAN-19 and -21, compared to the equivocal results with MDAN-16, suggests a minimum distance requirement between mu-opioid receptor and delta-opioid receptor recognition sites. This requirement may reflect the binding of MDAN-19 and -21 to mu-opioid receptor–delta-opioid receptor heterodimeric receptors that block reward but not antinociception.