Abuse liability, antinociceptive, and discriminative stimulus properties of IBNtxA

Abstract

ABSTRACTRationale IBNtxA (3-iodobenzoyl naltrexamine) is a novel μ opioid receptor (MOR) agonist structurally related to the classical MOR antagonist naltrexone. Recent studies suggest IBNtxA preferentially signals through truncated MOR splice variants, producing a unique pharmacological profile resulting in antinociception with reduced side effects, including no conditioned place preference (CPP) when tested at a single dose. IBNtxA represents an intriguing lead compound for preclinical drug development targeting truncated MOR splice variants but further evaluation of its in vivo pharmacological profileObjective The purpose of this study was to independently verify the analgesic properties of IBNtxA and to examine more completely the rewarding properties and discriminative stimulus effects of IBNtxA in order to more completely understand the in vivo effects of IBNtxA and further assess evaluate its abuse liability.Results IBNtxA was synthesized and compared to morphine in variety of mouse behavioral assays. 3 mg/kg IBNtxA was equipotent to 10 mg/kg morphine in a hot plate analgesia assay. In drug discrimination testing using mice trained to discriminate between 3 mg/kg IBNtxA and DMSO/saline vehicle, the κ agonist U-50488 fully substituted for IBNtxA. Classical μ agonist morphine, δ agonist SNC162, NOP agonist SCH 221510, and μ/NOP partial agonist buprenorphine each partially substituted for IBNtxA. IBNtxA up to 3 mg/kg did not produce a place preference in CPP. Pretreatment with 3 mg/kg IBNtxA but not 1 mg/kg IBNtxA attenuated acquisition of place preference for 10 mg/kg morphine. 3 mg/kg IBNtxA attenuated morphine-induced hyperlocomotion but did not alter naloxone-precipitated morphine withdrawal.Conclusions Overall IBNtxA has a complicated opioid receptor pharmacology in vivo. These results indicate that IBNtxA produces potent antinociception and has low abuse liability, likely driven by substantial κ agonist signaling effects.Competing Interest StatementThe authors have declared no competing interest.View Full Text