naltrindole-5--isothiocyanate and chlornaltrexamine

Subtypes of the delta opioid receptor (Oprd1) have been suggested based on pharmacology studies. However, these subtypes have not been confirmed biochemically using either receptor binding assays or molecular cloning. Naltrindole-5'-isothiocyanate (5'-NTII) is an irreversible opioid antagonist that appears to selectively inhibit the actions of a subset of delta opioid agonists in vivo, referred to as putative delta-2 agonists. The biochemical and anatomical selectivity of wash-resistant inhibition of binding of [(3)H]DAMGO (Oprm1), [(3)H]DPDPE (Oprd1, putative subtype 1 agonist), or [(3)H]deltorphin II (Oprd1, putative subytpe 2 agonist) in coronal sections was assessed using quantitative in vitro autoradiography following injection of 5'-NTII into the nucleus accumbens in rats. 5'-NTII decreased [(3)H]deltorphin II to a greater extent than the binding of the other two radioligands following administration of 0.05-2.5 nmol. The effects of 5'-NTII were largely confined to the nucleus accumbens; however, some loss in the ventral caudate was also noted. In contrast, administration of the nonselective opioid receptor alkylating antagonist beta-chlornaltexamine (beta-CNA) over a similar range of doses was found to be nonselective for either delta radioligand, and produced greater inhibition of Oprm1 relative to Oprd1 binding, consistent with the nonselective pharmacological activity of this antagonist. Although 5'-NTII inhibited [(3)H]deltorphin II binding to a greater extent, the binding of the other two radioligands was decreased over a similar range of doses. Absolute conclusions regarding the involvement of delta-2 opioid receptors in pharmacological or physiological effects based on studies with 5'-NTII should therefore be tempered, and for site-directed studies it would be best to employ doses of 0.5 nmol or lower.

Topics: Alkylation; Animals; Autoradiography; Binding, Competitive; Dose-Response Relationship, Drug; Drug Interactions; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Isothiocyanates; Male; Naltrexone; Narcotic Antagonists; Narcotics; Nucleus Accumbens; Oligopeptides; Phosphatidylethanolamines; Radioligand Assay; Rats; Rats, Inbred F344; Receptors, Opioid, delta; Transferases