Interactions between kappa opioid agonists and cocaine. Preclinical studies

Area of Science:

• Neuroscience
• Pharmacology
• Addiction Research

Background:

• Kappa opioid agonists are known to inhibit dopamine release.
• Previous studies suggest kappa opioid agonists may function as cocaine antagonists.
• Cocaine abuse remains a significant public health concern, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate the potential of kappa opioid agonists as functional antagonists of cocaine.
• To examine the effects of various kappa opioid agonists on cocaine self-administration in rhesus monkeys.
• To assess the side effect profiles and receptor interactions of these compounds.

Main Methods:

• Cocaine self-administration paradigm in rhesus monkeys.
• Administration of eight kappa opioid agonists (four arylacetamides and four benzomorphans) via continuous infusion over 10 days.
• Assessment of effects on cocaine and food-maintained responding, emesis, and sedation.
• Antagonism studies using kappa and non-selective opioid antagonists.

Main Results:

• Five kappa agonists (EKC, Mr2033, bremazocine, U50,488, enadoline) significantly decreased cocaine self-administration in a dose-dependent manner.
• Mixed kappa/mu opioid receptor agonists showed more consistent reductions in cocaine intake with fewer side effects than selective kappa agonists.
• Some kappa agonists also decreased food-maintained responding; tolerance developed to initial emesis and sedation.
• EKC and U50,488 did not consistently block cocaine's discriminative stimulus effects.

Conclusions:

• Certain kappa opioid agonists can reduce cocaine self-administration in non-human primates.
• Compounds with mixed kappa and mu opioid receptor activity appear more promising for reducing cocaine intake.
• Further research is needed to clarify if these reductions represent true antagonism of cocaine's abuse-related effects.