Kappa opioid agonists alter dopamine markers and cocaine-stimulated locomotor activity

To better understand the influence of κ-opioid agonists on the effects of cocaine, rats were treated with daily injections of the selective κ-opioid agonist U-69593 or bremazocine. In combination with 10mg/kg cocaine, both compounds, at a dose of 0.32 mg/kg, greatly diminished locomotor activity, and these effects were maintained over a period of 5 days. In addition, the response to a challenge injection of 10mg/kg cocaine several days after the end of κ-opioid agonist treatment with or without cocaine was markedly reduced. When naltrexone was given in combination with U-69593, it blocked the reduction in cocaine-induced locomotor activity after U-69593 treatment alone. However, a single injection of either κ-opioid agonist alone had no effect on cocaine-induced locomotion several days later (i.e. no long-term effects), suggesting that multiple injections of the κ-opioid agonist are needed to reduce the locomotor activating effects of cocaine other than acutely. In addition, treatment with the κ-opioid agonist U-69593 (0.32 mg/kg) over a 5-day period decreased dopamine transporter densities in the caudate putamen, and this was also blocked by co-administration of naltrexone.