Naloxone fails to produce conditioned place aversion in μ-opioid receptor knock-out mice

There is growing evidence that tonic activity of the opioid system may be important in the modulation of affective state. Naloxone produces a conditioned place aversion in rodents, an effect that is centrally mediated. Previous pharmacological data using antagonists with preferential actions at μ-, δ-, and κ-opioid receptors indicate the importance of the μ-opioid receptor in mediating this effect. We sought to test the μ-opioid receptor selectivity of naloxone aversion using μ-opioid receptor knock-out mice. μ-Opioid receptor knock-out and wild-type mice were tested for naloxone (10 mg/kg, s.c.) aversion using a place conditioning paradigm. As a positive control for associative learning, knock-out mice were tested for conditioned place aversion to a κ agonist, U50,488H (2 mg/kg, s.c.). Naloxone produced a significant place aversion in wild-type mice, but failed to have any effect in μ-opioid receptor knock-out mice. On the other hand, both knock-out and wild-type mice treated with U50,488H spent significantly less time in the drug-paired chamber compared to their respective vehicle controls. We conclude that the μ-opioid receptor is crucial for the acquisition of naloxone-induced conditioned place aversion. Furthermore, in a separate experiment using C57BL/6 mice, the δ-selective antagonist naltrindole (10 or 30 mg/kg, s.c.) failed to produce conditioned place aversion. Taken together, these data further support the notion that naloxone produces aversion by antagonizing tonic opioid activity at the μ-opioid receptor.