enkephalin--ala(2)-mephe(4)-gly(5)- and naltrindole-5--isothiocyanate

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

delta-Opioid receptors have been implicated in reinforcement processes and antagonists are available that produce long-lasting and selective antagonism of delta-opioid receptors in vivo. This experiment assessed the contribution of delta-opioid receptors to the antinociceptive and reinforcing properties of heroin. The effects of the irreversible delta-antagonist naltrindole-5'-isothiocyanate (5'-NTII) were evaluated on heroin self-administration and hot-plate antinociception in rats. 5'-NTII (10 nmol i.c.v.) shifted the dose-response curve for heroin self-administration downward, increasing the A(50) values on the ascending and descending limbs by approximately 0.5 log units and decreasing the maximum by 33%. 5'-NTII (40 nmol i.c.v.) shifted both limbs of the heroin self-administration dose-effect curve 1.2 log units to the right and decreased the maximum by 90%. Heroin self-administration gradually returned to baseline levels over 7 or 17 days after administration of 10 or 40 nmol 5'-NTII, respectively. 5'-NTII (40 nmol i.c.v.) decreased the self-administration of 0.17 mg/infusion cocaine by 40% while having no effect on responding maintained by 0.33 or 0.67 mg/infusion. 5'-NTII attenuated the antinociceptive effects of deltorphin (delta(2)) in a dose-dependent manner while having no effect on antinociception elicited after i.c. v. administration of [D-Pen(2),D-Pen(5)]-enkephalin (delta(1)) or [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (mu). In addition, the antinociceptive effects of heroin were not significantly affected by 5'-NTII (40 nmol i.c.v.). Therefore, 5'-NTII can attenuate the reinforcing effects of heroin at doses that do not affect its antinociceptive effects. Long-acting delta(2)-opioid antagonists may be beneficial in the treatment of heroin dependence or as adjuncts to reduce the abuse liability of opioid analgesics.

Topics: Analgesics, Opioid; Animals; Cocaine; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Heroin; Injections, Intraventricular; Isothiocyanates; Male; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain Measurement; Rats; Rats, Inbred F344; Receptors, Opioid, delta; Reinforcement, Psychology; Self Administration

Recently, we demonstrated that delta opioid binding sites are involved in the development of morphine tolerance and dependence. In our present work, we studied the effect of the potent and selective delta antagonist, naltrindole (NTI), and its nonequilibrium analog, naltrindole 5'-isothiocyanate (5'-NTII), on the development of morphine tolerance and dependence in mice. In the acute model, mice injected with 100 mg/kg of morphine sulfate s.c. displayed acute tolerance 4 hr later as evidenced by a greater than 3-fold increase of the ED50 of morphine sulfate when compared to that of control mice. The acute tolerance was accompanied by the development of acute physical dependence as seen by the dramatic decrease in the amount of naloxone required to precipitate withdrawal jumping. Likewise, in the chronic model s.c. implantation of morphine pellets (75 mg free base) for 3 days produced tolerance and physical dependence. The ED50 of morphine sulfate in this case was increased by about 19-fold and the amount of naloxone needed to precipitate withdrawal jumping was 40 times lower than that required for acutely dependent mice. The development of acute tolerance and dependence was suppressed markedly in mice pretreated with NTI before induction of tolerance and dependence with 100 mg/kg of morphine sulfate. Multiple administration of either NTI or 5'-NTII before and during implantation with morphine base pellets also inhibited substantially the development of morphine tolerance and dependence.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Drug Implants; Drug Tolerance; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Indoles; Isothiocyanates; Male; Mice; Morphinans; Morphine; Naltrexone; Narcotic Antagonists; Nociceptors; Receptors, Opioid; Receptors, Opioid, delta; Substance-Related Disorders; Thiocyanates