Cross‐species and Painless: Targeting truncated mu opioid receptor splice variants in the rat

Abstract

We recently synthesized a highly potent analgesic, 3′‐Iodobenzoylnaltrexamide (IBNtxA), which exhibited a favorable side effect profile devoid of respiratory depression, dependence, or rewarding behavior in a conditioned place preference assay. Analgesia was retained in a triple knockout mouse lacking traditional mu, delta, and kappa opioid receptors but retaining exon 11‐associated splice variants of MOR‐1; this analgesia was lost in an MOR‐1 exon‐11 knockout animal, implicating these variants in the drug's actions. We sought to determine whether IBNtxA exhibits similar pharmacology in the rat. IBNtxA retained high analgesic potency, and did not show any signs of respiratory depression. Saturation and competition studies in rat brain using 125IBNtxA demonstrated a site possessing a similar pharmacological profile to the site observed in mouse brain. We conclude that this target is not unique to the mouse, and that given the highly conserved splicing between the rat and human MOR‐1 genes, it is likely to have significant clinical relevance. This work was supported by a fellowship from the PhRMA Foundation to SG and grants from the National Institute on Drug Abuse (DA06241, DA02165, and DA07242) to GP.