Enhanced antinociception of mixed efficacy opioid peptidomimetics through P-glycoprotein modulation.

μ-Opioid receptor agonists are widely used in the treatment of pain, but produce many adverse effects. Studies suggest that co-administration of a μ-opioid receptor agonist with a δ-opioid receptor antagonist relieves pain with reduced adverse effects. We evaluated the antinociceptive effects of previously reported μ-opioid receptor agonist/δ-opioid receptor antagonist peptidomimetics in the acetic acid stretch assay and the warm water tail withdrawal (tail-flick) assay. All compounds produced anticonception in the ASSA; however, only 2 compounds, AAH8 and AMB47, produced antinociception in the tail-flick assay. the structurally similar analogs, AAH9 and AMB39, were ineffective. We hypothesized that this was due to pharmacokinetic differences. To test this hypothesis, we examined these compounds in the tail-flick assay after both intravenous and intracerebroventricular administration. Neither AAH9 nor AMB39 had any effect when given intravenously but both compounds produced antinociception after intracerebroventricular administration. AAH8 and AMB47 produced antinociceptive effects via all routes of administration. We hypothesized that crossing the blood-brain barrier was the limiting factor and tested the effects of AAH9 and AMB39 in combination with a P-glycoprotein inhibitor, Elacridar. After pretreatment with Elacridar, peripheral administration of AAH9 and AMB39 produced antinociception in the tail-flick assay. The dose-response curves for AAH8 and AMB47 were unaffected by pretreatment with Elacridar. These data suggest that even structurally similar peptidomimetics may have different pharmacokinetic properties that limit their antinociceptive effects. Understanding these pharmacokinetic properties may aid in the rational design of mixed efficacy peptidomimetic opioid ligands for the treatment of pain. SIGNIFICANCE STATEMENT: Many compounds fail out of drug development campaigns because of a lack of efficacy. One reason for this is the inability to reach the site of action. In this report, we describe 2 pairs of compounds with significantly different pharmacokinetic profiles and describe strategies for determining central nervous system penetration of opioid ligands.