Repeated Administration of Norbinaltorphimine Produces Cumulative Kappa Opioid Receptor Inactivation

Abstract

Kappa receptor activation by dynorphins contributes to the anxiogenic, dysphoric, and cognitive disrupting effects of repeated stress, suggesting that kappa receptor antagonists might have therapeutic utility in the treatment of stress disorders. Three classes of kappa antagonists have been distinguished: non-selective, selective-competitive (readily reversible), and non-competitive (receptor-inactivating); however, which would be the most effective medication has not been established. To assess the utility of receptor inactivating antagonists, we tested the effects of a range of doses in both male and female mice. As previously established, the antinociceptive effects of the kappa agonist U50,488 were blocked by a single injection of the long-acting antagonist norbinatorphimine (norBNI) (10 mg/kg i.p.) in male mice. Ten to 20-fold lower doses of norBNI were ineffective after a single administration, but daily administration of 1.0 or 0.5 mg/kg for 5 days completely blocked U50,488 antinociceptive effects. Daily administration of 0.1 mg/kg norBNI produced slowly accumulating inhibition and completely blocked the antinociceptive effect of U50,488 after 20–30 days. Estrogen reduces female sensitivity to kappa opioid effects, but 30 days of 0.1 mg/kg norBNI completely blocked U50,488 analgesia in ovariectomized mice. Receptor inactivation in both male and female mice treated for 30 days with 0.1 mg/kg norBNI persisted for at least 1-week. These results suggest that receptor-inactivating kappa antagonists are effective in both males and females when given at 100-fold lower doses than typically administered in preclinical studies. The enhanced safety of this low-dosing protocol has important clinical implications if receptor inactivating kappa antagonists advance in medication development.

Impact of Pharmacological Manipulation of the κ-Opioid Receptor System on Self-grooming and Anhedonic-like Behaviors in Male Mice

“…However, the intriguing pharmacodynamic and pharmacokinetic properties of these compounds (which can include slow onset, slow emergence of selectivity, and extremely long duration of action) can complicate the design and interpretation of in vivo studies (Endoh et al, 1992;Broadbear et al, 1994;Ko et al, 2003;Melief et al, 2011). It has been suggested that these longer-acting k-antagonists are "receptor-inactivating agents" that may function at least in part by producing complex downstream functional changes (Chavkin et al, 2019). Several groups have developed shorter-acting selective k-antagonists, with more "canonical" pharmacodynamics and pharmacokinetics, and classic competitive properties (Grimwood et al, 2011;Peters et al, 2011;Rorick-Kehn et al, 2014).…”

Regulation of Kappa Opioid Receptor Inactivation Depends on Sex and Cellular Site of Antagonist Action

“…This potentially safer low-dosing strategy was previously demonstrated to be effective in males (Chavkin et al, 2019).…”

“…The release of endogenous opioid dynorphin peptides throughout the brain contributes to these adverse behavioral effects (Ehrich et al, 2015;Abraham et al, 2018a). For this reason, researchers have explored using kappa opioid antagonists as antidepressants and anti-addiction therapeutics in both pre-clinical research and human clinical trials (Buda et al, 2015;Carrol & Carlezon, 2013;Lowe et al, 2014;Chavkin et al, 2019). Three different forms of KOR antagonists have been identified: nonselective (e.g.…”

“…This KOR-inactivating process can be blocked by inhibitors of JNK or the PLA2 activity of PRDX6 and can be detected with ROS sensors, including the genetically encoded indicator HyPerRed fluorescent protein indicator which sensitively reports production of hydrogen peroxide (Schattauer et al, 2017a;Schattauer 2019). ROS-dependent inactivation of KOR can be produced by administering a single high dose of norBNI, or by administering repeated low doses of norBNI (Chavkin et al, 2019). This action is due to collateral agonist activity, an effect wherein a compound acts as an antagonist by selectively activating a subcomponent of receptor signaling, in turn inactivating subsequent signaling at that receptor (Kenakin, 2005;Bruchas et al, 2007).…”

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“…The antagonist-receptor complex formation happens by binding the small molecule to the active site or to the allosteric site on the receptor. Depending on the longevity of the antagonist-receptor complex, the activity of the antagonist compounds may be reversible or irreversible [3]. One main group of the receptors into the human cells is the opioid receptors (OR).…”