In vivo effects of μ-opioid receptor agonist/δ-opioid receptor antagonist peptidomimetics following acute and repeated administration

Abstract

Background and Purpose: Agonists at μ-opioid receptors (μ-receptors) are used for pain management but produce adverse effects including tolerance, dependence and euphoria. The co-administration of a μ-receptor agonist with a δ-opioid receptor (δ-receptor) antagonist has been shown to produce antinociception with reduced development of some side effects. We characterized the effects of three μ-receptor agonist/δ-receptor antagonist peptidomimetics in vivo after acute and repeated administration to determine if this profile provides a viable alternative to traditional opioid analgesics. Experimental Approach: Three μ-receptor agonist / δ-receptor antagonist peptidomimetics, AAH8, AMB46 and AMB47, and morphine were evaluated for the development of tolerance and dependence after 5 days of twice daily treatment with escalating doses of drug (10–50 mg·kg −1 ). Antinociceptive effects were measured in the warm water tail withdrawal assay before and after repeated drug treatment. Physical dependence was evaluated by naltrexone-precipitated withdrawal jumping. The rewarding effects of AAH8 were evaluated using a conditioned place preference (CPP) assay with twice daily conditioning sessions performed for 5 days. Key Results: Morphine, AAH8, AMB47 and AMB46 all demonstrated acute antinociceptive effects, but repeated administration only produced tolerance in animals treated with morphine and AMB46. Injection of naltrexone precipitated fewer jumps in mice treated repeatedly with AAH8 as compared with morphine, AMB47 or AMB46. Conditioning with morphine, but not AAH8, produced significant CPP. Conclusions and Implications: AAH8 may be a better alternative than traditional opioid analgesics, producing antinociception with less development of tolerance and dependence and may be less rewarding than morphine.