Peripherally Restricted Opioid Analgesics

New Developments in Peripherally Restricted Opioid Analgesics

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.

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

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.

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).

“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.

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.  


Here is another article about the same findings:

Opioid receptors outside the brain targeted in rats; new direction for painkillers — ScienceDaily

senior study author Nathaniel Jeske of the University of Texas Health Science Center at San Antonio said, “Being able to increase the responsiveness of peripheral opioid receptor systems could lead to a reduction in systemic opioid administration, thereby reducing the incidence of side effects.”

Most clinical opioids currently available target mu opioid receptors, including those located in the brain, and therefore have a high potential for abuse.

By contrast, drugs targeting delta opioid receptors in the peripheral nervous system rather than the brain and spinal cord produce fewer side effects in animals and have a much lower abuse potential.

However, delta opioid receptors in peripheral tissues only become activated in the presence of inflammation.

Here’s the catch: Delta opioid receptors behave differently than mu opioid receptors, so we can’t predict the effects.

They found that a protein called GRK2 binds to and prevents delta opioid receptors on rat sensory neurons from responding normally to opioids, but when these peripheral neurons were exposed to a natural inflammatory molecule called bradykinin, GRK2 moved away from the delta opioid receptors, setting off a biochemical reaction that restored the functioning of these receptors.

Moreover, rats with reduced GRK2 levels in peripheral sensory neurons regained sensitivity to the pain-relieving effects of a drug that activates delta opioid receptors without the need for an inflammatory trigger.

The findings expand the known function of GRK2 to include a role in inhibiting the function of delta opioid receptors in peripheral sensory neurons. Moving forward, the researchers will attempt to replicate the findings using human tissues.  


And here is the actual scientific article:

GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity.

Brackley AD, Gomez R, Akopian AN, Henry MA, Jeske NA.

Cell Rep. 2016 Aug 24. pii: S2211-1247(16)31030-0. doi: 10.1016/j.celrep.2016.07.084.

PMID: 27568556

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