Kappa Opioid Receptor Signaling Contributes to Re‐escalation of Oxycodone Self‐administration Under Extended Access Conditions

Abstract

Prescription opioid abuse is a significant global problem, and opioid addiction is well‐characterized by compulsive drug seeking, motivational withdrawal and chronic relapse. The goal of this study was to investigate escalation of opioid intake with extended access to intravenous oxycodone self‐administration and re‐engagement of drug seeking (re‐escalation) following detoxification. Male Wistar rats were randomly assigned to short‐access (ShA, 1‐h) and long‐access (LgA, 12‐h) groups and trained to self‐administer oxycodone (0.15 mg/kg/infusion) using a fixed‐ratio 1 (FR1) response contingency and evaluated on a progressive‐ratio (PR) procedure incorporating dose‐substitution of oxycodone (0.06–0.3 mg/kg/infusion). Both groups underwent an abstinence period (4 weeks) and were tested for re‐escalation. Rats given LgA to oxycodone earned more infusions than rats trained with ShA during acquisition. PR test results demonstrated an increase in drug‐intake and breakpoints in rats assigned to LgA training relative to rats assigned to ShA training. All rats exhibited high levels of drug seeking upon re‐engagement; however, LgA rats failed to de‐escalate drug intake following the abstinence period. Previous findings show kappa opioid receptor (KOR) mediated disruption in GABAergic signaling in the central nucleus of the amygdala (CeA) is observed after acute (24‐h) withdrawal from escalated cocaine self‐administration. To investigate KOR dysregulation following acute oxycodone withdrawal, electrophysiological recordings were performed in CeA slices. The selective KOR agonist U‐50488 decreased GABAergic signaling in both ShA and LgA rats, and this effect was blocked by KOR antagonist nor‐binaltorphimine (nor‐BNI). Applied alone, norBNI increased GABAergic signaling, suggesting tonic KOR activity. These findings further support the conclusion that access duration differentially impacts the acquisition and maintenance of the self‐administration of oxycodone, and suggest that KOR‐mediated signaling during oxycodone dependence may be distinct from that of other drugs of abuse.Support or Funding InformationNIH grant DA035281