Dezocine is a Biased Ligand without Significant Beta-Arrestin Activation of the mu Opioid Receptor

Abstract

Dezocine is an opioid that was used in clinical practice for acute pain management in the US (1986US ( to 2011 and is currently in use in China. It is not listed as a controlled substance in the US due to no reported cases of addiction. Dezocine is a partial agonist at the mu opioid receptor (MOR); however, it is unclear whether dezocine can activate both the G protein pathway and the beta-arrestin pathway. In this study we hypothesized that dezocine does not activate the beta-arrestin pathway, which could be the potential molecular mechanism by which dezocine is not addictive or at least less addictive than other classic opioids. Both morphine, a MOR full agonist and buprenorphine, a partial MOR agonist similar to dezocine, were used for comparison purposes. The major side effects of dezocine in clinical usage are its gastrointestinal side effects and first pass effects; therefore, we explored the possibility of administering dezocine intranasally in rodents to demonstrate the feasibility of intranasal administration for new clinical usage purposes. With proper formulation it is possible to administer dezocine intranasally to achieve a high concentration in the brain in the rodent model. The results indicate that dezocine does not activate the betaarrestin pathway in MOR. Intranasal delivery of dezocine achieves a much higher medication concentration in the blood and brain as compared to intraperitoneal injection. It also persists a longer time before it falls below detection in the blood. This study provides a possible explanation of why dezocine is not addictive or at least less addictive than other commonly used opioids. This study also demonstrates that intranasal administration offers an alternative strategy for its potential clinical applications. MethodsAll the chemicals used in this study were commercially obtained and were either analytical or pharmaceutical grade with more than 98% purity. Nanodezocine (dezocine complexed with 2-hydroxypropylγ-cyclodextrin) is a patented formulation produced in our laboratory [9]. HTLA cells, an HEK293 cell line stably expressing a tTA-dependent luciferase reporter and a beta-arrestin-TEV fusion gene, were kindly provided by the laboratory of Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill [10]. The animal protocols were approved by the Institutional

Non‐scheduled short‐acting opioid to taper off opioids?

“…In the future drug development for addiction therapy, short‐acting regimen for an easy taper down or taper off opioids should be explored. We and others have found that dezocine, a previously FDA approved opioid, is a potential candidate for such purposes (Dalgan, average half‐life 2.2 h) 10–13 . It was discontinued in the US market around 2011 following its substance matter patent expiration.…”

“…Unlike other opioids, there are no reports in the English language medical literature of addiction or abuse or associated death with dezocine despite decades of clinical usage. It is a partial mu opioid receptor (MOR) agonist without significant beta‐arrestin pathway activation and is a kappa opioid receptor antagonist 13,14 . It also inhibits both norepinephrine and serotonin transporter proteins, comparable to nisoxetine, an anti‐depressive medication with analgesia properties 14 .…”

“…We and others have found that dezocine, a previously FDA approved opioid, is a potential candidate for such purposes (Dalgan, average half‐life 2.2 h). 10 , 11 , 12 , 13 It was discontinued in the US market around 2011 following its substance matter patent expiration. Unlike other opioids, there are no reports in the English language medical literature of addiction or abuse or associated death with dezocine despite decades of clinical usage.…”

“…It is a partial mu opioid receptor (MOR) agonist without significant beta‐arrestin pathway activation and is a kappa opioid receptor antagonist. 13 , 14 It also inhibits both norepinephrine and serotonin transporter proteins, comparable to nisoxetine, an anti‐depressive medication with analgesia properties. 14 Depression is one hallmark of opioid withdrawal syndrome, and a potential reason for relapse.…”