A Centrally Active, Peripherally Available Mixed Efficacy MOR/DOR Ligand that Displays Reduced Development of Negative Side Effects

Abstract

Mu‐opioid receptor (MOR) agonists have long been used in the treatment of pain and are currently the gold standard for pain management in the clinic. While these compounds produce considerable analgesia, their use produces many adverse effects, such as the development of antinociceptive tolerance, physical dependence, euphoria, and constipation. It has been suggested that the co‐administration of a MOR agonist with a delta opioid receptor (DOR) antagonist may produce MOR‐mediated analgesia with reduced side effects. However, administering drug cocktails has considerable complications related to potential diverse pharmacokinetic properties of the two chemical entities. We therefore explored the development of multifunctional ligands that display both MOR agonism and DOR antagonism in a single molecule. We have previously reported a cyclic peptide with a C‐terminal β‐glucoserine, VRP26, which displays the desired MOR agonist/DOR antagonist profile in vitro and produces opioid mediated antinociception in the warm water tail withdrawal assay after peripheral administration in male C57BL/6N mice. The goals of the current study were to evaluate whether VRP26: 1) crosses the blood brain barrier and 2) produces tolerance, dependence, rewarding effects, and constipation. The effects of VRP26 on centrally‐mediated behaviors in nitroglycerin‐induced hyperalgesia assay and the tail suspension test were evaluated. Tolerance and dependence were evaluated following continuous VRP26 infusion for 7 days, rewarding effects were evaluated in a conditioned place preference assay, and constipation was evaluated by fecal bolus production following acute drug administration. VRP26 reversed nitroglycerin‐induced hyperalgesia and attenuated antidepressant‐like effects induced by the DOR agonist SNC80. Unlike fentanyl, 7 day continuous administration of VRP26 failed to produce a rightward shift in the antinociceptive dose response curve and produced fewer signs of naltrexone‐precipitated withdrawal than fentanyl. VRP26, unlike fentanyl, did not produce significant conditioned place preference. VRP26 also was less potent that morphine in producing constipating effects. In conclusion, VRP26 produces centrally mediated antinociception, with limited development of antinociceptive tolerance, physical dependence, and rewarding effects. Further, VRP26 has a greater therapeutic index between antinociceptive and constipating effects, demonstrating potential increased tolerability. VRP26 demonstrates proof of concept that mixed efficacy opioid ligands may be better alternatives to traditional opioid analgesics for chronic pain management, producing pain relief with limited negative effects.Support or Funding InformationThis work was funded by NIH Grant DA003910. J.P.A was supported by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award T32 DA007267. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.