Abstract
Rationale: In humans, µ-opioid-cocaine combinations (speedballs) have been reported to heighten pleasurable effects and result in greater abuse potential compared to either drug individually. Emerging evidence in animals suggests that the ability of µ-opioids to enhance the reinforcing effects of cocaine might be independent of their µ-intrinsic efficacy even though µ-agonist efficacy appears to be a determinant in the reinforcing effects of µ-opioids themselves.
Objectives: This study examd. the relationship between agonist efficacy, self-administration, and the enhancement of cocaine self-administration using the high-efficacy µ-agonist etonitazene.
Materials and methods: Rhesus monkeys self-administered cocaine, heroin, etonitazene, and opioid-cocaine combinations under a progressive-ratio schedule of i.v. drug injection.
Results: Unlike cocaine and heroin, etonitazene did not maintain consistent self-administration at any dose tested (0.001-1.0 µg/kg/injection). However, combining etonitazene (0.1-1.0 µg/kg/injection) with cocaine (0.01 and 0.03 mg/kg/injection) enhanced cocaine self-administration, and this enhancement was attenuated by naltrexone. These effects are similar to those obtained by combining non-reinforcing doses of heroin and cocaine. Antagonism of etonitazene-cocaine and heroin-cocaine self-administration by naloxonazine was short lasting and was not maintained after 24 h (when naloxonazine's purported µ1 subtype antagonist effects are thought to predominate).
Conclusions: The results suggest that high µ-agonist efficacy does not guarantee consistent drug self-administration and that the ability of µ-agonists to enhance cocaine self-administration does not depend exclusively on reinforcing efficacy. Moreover, the results do not support a major role for µ1-receptor mechanisms in either etonitazene- or heroin-induced enhancement of cocaine self-administration.