Abstract

Mu opioid receptor (MOPr) agonists are well-known and frequently used clinical analgesics but are also rewarding due to their highly addictive and often abusive properties. This may lead to opioid use disorder (OUD) a disorder that effects millions of people worldwide. Therefore, novel compounds are urgently needed to treat OUD. As opioids are effective analgesics and OUD often occurs in conjunction with chronic pain, these novel compounds may be opioids, but they must have a low abuse liability. This could be mediated by diminishing or slowing blood-brain barrier transport, slowing target receptor binding kinetics, and showing a long half-life. NKTR-181 is a PEGylated oxycodol and a MOPr agonist that has slowed blood-brain barrier transport, a long half-life, and diminished likeability in clinical trials. In this study, we examined the signaling and behavioral profile of NKTR-181 in comparison with oxycodone to determine whether further therapeutic development of this compound may be warranted. For this preclinical study, we used a number of in vitro and in vivo assays. The signaling profile of NKTR-181 was determined by the electrophysiological assessment of MOPr-Ca2+ channel inhibition in the nociceptive neurons of rodent dorsal root ganglia. Heterologous cell-based assays were used to assess biased agonism and receptor trafficking. Different rodent behavioral models were used to define the NKTR-181-induced relief of effective and reflexive nociception and drug-seeking behavior as assessed by an intravenous self-administration (IVSA) of NKTR-181. We found that NKTR-181 and oxycodone are partial agonists in G-protein signaling and Ca2+ channel inhibition assays and promote limited MOPr desensitization. However, NKTR-181 inhibits Ca2+ channels by a different mechanism than oxycodone and induces a different pattern of arrestin recruitment. In addition, NKTR-181 has a slower receptor on-rate and a slower rate of Ca2+ channel coupling than oxycodone. This signaling profile is coupled with a slower onset of antinociception and limited drug-seeking behavior in comparison with oxycodone. Together with its known long half-life and slow blood-brain barrier transport, these data suggest that NKTR-181 could be further studied as a pharmacotherapeutic treatment modality for OUD.

Highlights

  • The prescription, diversion, and illicit use or production of opioid analgesics and opioids have emerged as a major societal concern fueling a concerted effort to identify novel treatments for chronic pain and the development of more effective treatments for those afflicted with substance use disorders

  • Our studies show that there could be interest in developing this drug as a novel treatment for Opioid use disorder (OUD)

  • The findings that NKTR-181 has a longer half-life, slow CNS entry, partial agonist activity and low reinforcement effects, yet exhibits efficacy as an analgesic, providing evidence that this drug may be an effective abuse deterrent treatment

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Summary

Introduction

The prescription, diversion, and illicit use or production of opioid analgesics and opioids have emerged as a major societal concern fueling a concerted effort to identify novel treatments for chronic pain and the development of more effective treatments for those afflicted with substance use disorders. Opioid use disorder (OUD) affects over 27 million people worldwide (2016) and is considered as an epidemic in the USA as more than 100 people die daily due to opioid-related death. Current medications used for treating OUD include various formulations of the long-acting opioid agonists such as methadone and buprenorphine or the nonselective opioid antagonist naltrexone. Each of these treatments has its limitations: methadone is only dispensed from licensed clinics and patients have to travel daily to get their dose. New treatment options are needed for those who are actively seeking treatments to manage their OUD

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