Antagonism of δ₂-Opioid Receptors by Naltrindole-5′-isothiocyanate Attenuates Heroin Self-Administration but Not Antinociception in Rats1

Abstract

δ-Opioid receptors have been implicated in reinforcement processes and antagonists are available that produce long-lasting and selective antagonism of δ-opioid receptors in vivo. This experiment assessed the contribution of δ-opioid receptors to the antinociceptive and reinforcing properties of heroin. The effects of the irreversible δ-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 A₅₀ 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 (δ₂) in a dose-dependent manner while having no effect on antinociception elicited after i.c.v. administration of [d-Pen²,d-Pen⁵]-enkephalin (δ₁) or [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (μ). 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 δ₂-opioid antagonists may be beneficial in the treatment of heroin dependence or as adjuncts to reduce the abuse liability of opioid analgesics.