Effects of Mixed-Action κ/μ Opioids on Cocaine Self-Administration and Cocaine Discrimination by Rhesus Monkeys

Abstract

k-Opioid agonists may functionally antagonize some behavioral effects of cocaine, but the role of mixed k/m receptor activity is unclear. The effects of three mixed k/m agonists (MCL-101, (À)cyclorphan, and Mr2034) and one k-selective agonist (enadoline) on cocaine selfadministration and cocaine discrimination were compared in rhesus monkeys. Acute treatment with all k agonists dose dependently reduced cocaine-maintained responding and produced a downward shift in the cocaine self-administration dose-effect curve (0.001-0.32 mg/kg/inj, i.v.). During 7 days of chronic treatment, (À)cyclorphan (0.0032-0.032 mg/kg/h) and MCL-101 (0.0032-0.032 mg/kg/h) each dose dependently reduced cocaine self-administration maintained by a dose near the peak of the cocaine self-administration doseeffect curve. MCL-101 (0.032 mg/kg/h) produced selective and sustained decreases in cocaine self-administration, whereas (À)cyclorphan (0.032 mg/kg/h) had selective but transient effects. In addition, these mixed k/m agonists produced fewer side effects (some salivation) than the k-selective agonist (sedation, salivation, emesis). However, none of these k agonists substituted for or antagonized cocaine's discriminative stimulus effects in monkeys trained to discriminate cocaine (0.4 mg/kg, i.m.) from saline. Thus, k and mixed k/m-opioid agonists may reduce cocaine self-administration without altering cocaine's discriminative stimulus effects. Mixed k/m agonists appear to offer some advantages over selective k agonists as potential treatments for cocaine abuse.

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

“…Enadoline, a selective kappa-opioid receptor agonist, also did not attenuate the effects or selfadministration of intravenous cocaine (Walsh et al, 2001). Chronic treatment with the mixed kappa-and mu-opioid receptor agonist MCL-101, however, did reduce cocaine self-administration in a non-human primate model (Bowen et al, 2003).…”

Effects of the Mixed Mu/Kappa Opioid Nalbuphine on Cocaine-Induced Changes in Subjective and Cardiovascular Responses in Men

“…In preclinical studies, kappa opioids attenuated many of the abuse-related and locomotor-activating effects of cocaine, and these findings suggested that kappa opioids might be useful for the clinical treatment of cocaine abuse (Archer et al, 1996; see for a review Mello and Negus, 2000). Cocaine self-administration studies in non-human primates indicated that kappa opioids with mu receptor activity reduced cocaine selfadministration more effectively, and with fewer adverse side effects, than kappa selective opioids Bowen et al, 2003). Accordingly, we chose nalbuphine from the very limited number of kappa opioids approved for clinical use by the FDA.…”

“…Both EKC and Mr2033 appear to act as low efficacy agonists at mu opioid receptors and as high efficacy agonists at kappa opioid receptors. Subsequent studies in rhesus monkeys confirmed that mixed mu/kappa opioids were more effective in reducing cocaine selfadministration than kappa selective opioids, and produced minimal side effects (Bowen et al, 2003). Taken together, these studies suggested that mixed mu/kappa opioids may provide a useful approach to treatment of cocaine abuse.…”

“…In contrast, in rhesus monkeys, chronic treatment with nalbuphine (0.1 mg/kg/h or 1.0 or 3.0 mg/kg/day), as well as several other mixed mu/kappa opioids, significantly reduced cocaine self-administration over 7 to 10 days (Mello et al, 1993;Negus et al, 1997;Mello and Negus, 1998b;Negus and Mello, 2002;Bowen et al, 2003). The acute effects of mixed mu/kappa agonists on cocaine's reinforcing and discriminative stimulus effects have been less consistent.…”

“…The acute effects of mixed mu/kappa agonists on cocaine's reinforcing and discriminative stimulus effects have been less consistent. In a drug self-administration procedure where treatment drug effects on multiple unit doses of cocaine could be evaluated in two or three sessions (Caine et al, 2000), the mixed mu/ kappa agonists (À)cyclorphan, Mr2034, and MCL-101 dose dependently decreased cocaine self-administration with minimal side effects (Bowen et al, 2003). However, acute administration of the same mixed mu/kappa agonists that reduced cocaine self-administration did not significantly attenuate cocaine discrimination, and did not produce rightward shifts in the cocaine discrimination dose-effect curve in rhesus monkeys (Negus and Mello, 1999;Bowen et al, 2003).…”