A role for kappa‐, but not mu‐opioid, receptor activation in acute food deprivation‐induced reinstatement of heroin seeking in rats

Stress is considered to be one of the major triggers to drug relapse, even after prolonged periods of abstinence. In rats, the activation of stress‐related brain systems, including corticotropin‐releasing factor and norepinephrine, is critical for stress‐induced reinstatement of extinguished drug seeking, an animal model for drug relapse. In addition, there are strong indications that activation of the endogenous opioid system is important for the effects of stress on drug seeking. More specifically, activation of the dynorphin/kappa opioid receptor (KOR) system is critically involved in the reinstatement of cocaine seeking following exposure to stressors, such as footshock, forced swimming or social stress. However, studies on the role of the dynorphin/KOR system in stress‐induced reinstatement of heroin seeking are scarce. Here, rats were trained to self‐administer heroin (0.1 mg/kg/infusion) for 10 days. Drug seeking was then extinguished and the rats were tested for acute (21 hours) food deprivation‐induced reinstatement of heroin seeking. In two separate experiments, rats were injected with the mu‐opioid receptor (MOR) antagonist, naltrexone (0.0, 1.0, 10.0 mg/kg; s.c.) or the KOR antagonist, norBNI (0.0, 1.0, 10.0 mg/kg; i.p.) before the reinstatement test. Naltrexone treatment did not affect stress‐induced reinstatement. In contrast, treatment with norBNI dose‐dependently attenuated food deprivation‐induced reinstatement of heroin seeking. These results support the hypothesis that activation of KOR, but not MOR, is critically involved in stress‐induced reinstatement of drug seeking.