Selectivity of δ- and κ-opioid ligands depends on the route of central administration in mice

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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 δ-and κ-opioid receptors have been proposed to arise from different organizational states that include oligomeric δ-κ heterodimers and homomeric δ and κ receptors. In view of the evidence for analgesia mediated by δ-κ heterodimers in the spinal cord, but not the brain, we have investigated the selectivity of pharmacologically selective δ and κ antagonists in mice by both i.t. and i.c.v. routes of administration to evaluate changes in selectivity. Using pharmacologically selective δ (benzylidenenaltrexone, naltrindole, and naltriben) and κ (norbinaltorphimine) antagonists versus δ ([D-Pen2,D-Pen5]-enkephalin and deltorphin II) and κ [3,4-dichloro-N-methyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]- benzeneacetamide (U50488) and bremazocine] agonists, the δ-1/δ-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 δ-κ heterodimers and supraspinal homomeric δ and κ 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.

Original languageEnglish (US)
Pages (from-to)166-171
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - Jul 2007


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