title: Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores.
abstract: 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.
authors: Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, United States. lenardnr@pbrc.edu
authors: Natalie R
authors: NR
authors: Lenard
authors: David J
authors: DJ
authors: Daniels
authors: Philip S
authors: PS
authors: Portoghese
authors: Sandra C
authors: SC
authors: Roerig
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003213:Conditioning, Psychological / Q000502:physiology; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010111:Oxymorphone / Q000031:analogs & derivatives* / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists*
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D009271:Naltrexone; D009020:Morphine; D010111:Oxymorphone