New Developments in Peripherally Restricted Opioid Analgesics

This study provides evidence to explain activation of peripheral opioid receptors by inflammation.

Opioid analgesics act by binding to mu- (µ), delta- (δ) and kappa- (κ) opioid receptors located in the central and peripheral nervous system. 

Currently available opioid analgesics, including morphine, the most commonly used opioid for chronic pain management, readily cross the blood-brain-barrier (BBB) to bind to µ-opioid receptors in the central nervous system (CNS) where they elicit both analgesic and adverse effects, including tolerance and physical dependency.1,2

Pain modeling and animal studies provide proof-of-concept that opioid analgesics which do not cross the BBB and are therefore peripherally restricted, can maintain analgesic efficacy, but with reduced CNS side effects, a property of interest for chronic pain therapy.3,4

While numerous research efforts have been directed to the development of peripherally restricted opioid analgesics over the past decade, none have advanced to clinical use.1,2,5

A key challenge is that a state of inflammation is required to activate peripheral opioid receptors. Unraveling the role of inflammation in the activation of peripheral opioid receptors will close a major gap in knowledge and provide potential targets for the development of peripherally restricted opioid analgesics.

In an article published in Cell Reports in August 2016, researchers at the University of Texas Health Science Center identified a key protein, the G protein coupled receptor kinase 2 (GRK2), which modulates activity of the peripheral δ-opioid receptor (DOR).6

“We targeted the DOR receptor system because it appears to have the fewest systemic side effects, either via peripheral or central receptor activation,” explained Nathaniel A. Jeske, PhD, Director of Research at the University of Texas Health Science Center at San Antonio, and senior author in this study.

“However, depending on the type of pain experienced, either mechanical, chemical or thermal, one could target a specific opioid receptor system with peripherally restrictive agonists to alleviate one or more pain modalities,” he added.

In the non-inflamed tissue, GRK2 is bound to the DOR, rendering it inactive to bind to an opioid analgesic. However, in the inflamed tissue, GRK2 is displaced, and able to bind to an opioid analgesic.

Using an animal model, the researchers were able to demonstrate that bradykinin -naturally produced in response to injury and tissue inflammation- triggers the uncoupling of GRK2 from the DOR.

Binding of the displaced GRK2 to another cellular protein, the Raf kinase inhibitory protein, results in the sequestration of GRK2, allowing opioid analgesics to bind DORs.

This study provides the first compelling evidence explaining activation of peripheral opioid receptors during inflammation. It also provides potential new targets for the development of peripherally restricted DOR agonists.

“There are several candidate compounds that target DOR currently under pharmaceutical development,” Dr. Jeske said, adding that “increasing research towards DOR-specific compounds could prove important clinically to pain patients in the future. Our work would likely provide more benefit to those experiencing chronic pain.”

Given that the currently available opioid analgesics for chronic pain management are highly problematic, this new development can potentially provide alternative options that have reduced side effects and lower risk for tolerance and abuse potential. 

Summary and Clinical Applicability

This study provides evidence to explain activation of peripheral opioid receptors by inflammation. Key proteins identified are potential therapeutic targets for the development of safer peripherally restricted opioid analgesics for chronic pain management.

Related Articles

Follow @ClinicalPainAdv


  1. Sehgal N, Smith HS, Manchikanti L. Peripherally acting opioids and clinical implications for pain control. Pain Physician. 2011;14(3):249-258.
  2. Vadivelu N, Mitra S, Hines RL. Peripheral opioid receptor agonists for analgesia: a comprehensive review. J Opioid Manag. 2011;7(1):55-68.
  3. Spetea M, Schmidhammer H. Recent advances in the development of 14-alkoxy substituted morphinans as potent and safer opioid analgesics. Curr Med Chem. 2012;19(15):2442-2457.
  4. Charles A, Pradhan AA. Delta-opioid receptors as targets for migraine therapy. Curr Opin Neurol. 2016;29(3):314-319.
  5. Stein C. Targeting pain and inflammation by peripherally acting opioids. Front Pharmacol. 2013;4:123.
  6. Brackley AD, Gomez R, Akopian AN, Henry MA, Jeske NA. GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity. Cell Rep. 2016. pii: S2211-S1247(16)31030-0.