Selectivity of delta- and kappa-opioid ligands depends on the route of central administration in mice.
The existence of heterodimeric opioid receptors has introduced greater complexity to the in vivo characterization of pharmacological selectivity of agonists by antagonists. Because of the possibility of cooperativity between receptors organized as heterodimers, it is conceivable that selective antagonists may antagonize an agonist bound to a neighboring, allosterically coupled receptor. As a consequence, the in vivo selectivity of an opioid antagonist may depend on the organizational state of receptors that mediate analgesia. In this regard, phenotypic delta- and kappa-opioid receptors have been proposed to arise from different organizational states that include oligomeric delta-kappa heterodimers and homomeric delta and kappa receptors. In view of the evidence for analgesia mediated by delta-kappa heterodimers in the spinal cord, but not the brain, we have investigated the selectivity of pharmacologically selective delta and kappa antagonists in mice by both i.t. and i.c.v. routes of administration to evaluate changes in selectivity. Using pharmacologically selective delta (benzylidenenaltrexone, naltrindole, and naltriben) and kappa (norbinaltorphimine) antagonists versus delta ([D-Pen(2),D-Pen(5)]-enkephalin and deltorphin II) and kappa [3,4-dichloro-N-methyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide (U50488) and bremazocine] agonists, the delta-1/delta-2 selectivity ratios were found to be dependent on the route of administration (i.t. versus i.c.v.). The data from different routes of administration suggest that differences in molecular recognition between spinal delta-kappa heterodimers and supraspinal homomeric delta and kappa receptors may contribute to the divergent selectivity ratios of selective antagonists. In view of the observed tissue-dependent selectivity, we suggest that multiple opioid antagonists be employed routinely in establishing agonist selectivity in vivo.
Lunzer
Mary M
MM
Department of Medicinal Chemistry, University of Minnesota, 308 Harvard St. S.E., Minneapolis, MN 55455, USA.
Portoghese
Philip S
PS
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000008:administration & dosage; D000818:Animals; D001597:Benzylidene Compounds / Q000008:administration & dosage; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000008:administration & dosage; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives; D009292:Narcotic Antagonists / Q000008:administration & dosage*; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*
D001597:Benzylidene Compounds; D008024:Ligands; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; C068868:naltrindole benzofuran; C077358:7-benzylidenenaltrexone; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D020881:Enkephalin, D-Penicillamine (2,5)-; C055382:naltrindole