Current strategies toward safer mu opioid receptor drugs for pain management

ABSTRACT

Introduction: Pain relief remains a major public health challenge. The most efficient available painkillers are opioids targeting the mu opioid receptor (MOR). MORs are expressed in the areas of the brain [including pain and respiratory centers] that are important for processing reward and aversion. Thus, MOR activation efficiently alleviates severe pain, but the concomitant reward and respiratory depressant effects pose a threat; patients taking opioids potentially develop opioid addiction and high risk for overdose.

Areas covered: Ongoing efforts to generate safer opioid analgesics are reviewed here. The design of biased compounds that trigger MOR induced G protein over β-arrestin signaling, peripheral opioids, drugs targeting MORs in heteromers and drugs enhancing endogenous opioid activity are discussed.

Expert opinion: There is evidence that throttling MOR signaling may lead to an era of opioids that are truly efficient painkillers with lower side effects and risk of overdose. However, few of the drugs derived from the advanced approaches outlined here, are getting approval by regulatory committees for use in clinical settings. Thus, there is an urgent need to (i) better clarify mechanisms underlying the hazardous physiological effects of MOR activation, and (ii) fully validate the safety of these new MOR-based therapies.

KEYWORDS:

• Opioid receptor
• biased agonism
• allosteric
• pain
• addiction
• opiate
• GPCR
• drug
• discovery
• heteromer
• peripherally limited opioid
• pH-dependent agonist and endogenous opioid
• analogue

Article Highlights

• Opioid analgesics are unsurpassed painkillers but are hampered by severe adverse effects

• Emerging biased agonists may soon be available as safer opioids

• There are new approaches to the development of peripherally limited opioids as safer painkillers

• Strategies to develop safer opioid pain killers include targeting MORs in heteromers, MOR allostery and the development of endogenous opioid peptide analogues

• There is an urgent need to clarify the mechanisms underlying the unwanted effects of MOR activation; this may pave safer ways to target MORs

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This work was funded by National Institute of Health (National Institute of Drug Abuse Grant number. 05010 and National Institute on Alcohol Abuse and Alcoholism, Grant number 16658 awarded to BL Kieffer), the Canada Fund for Innovation and the Canada Research Chairs awarded to E Darcq and BL Kieffer.