A New Opioid Targets Active Sites of Inflammation to Relieve Pain – by Nathan T. Fried on 23 Mar 2017
Summary: NFEPP binds and activates mu-opioid receptors only at low pH, soothing pain in rats without typical side effects
Adverse effects of opioids can occur because the drugs act at both injured and healthy tissue, but if researchers could find a way to direct opioids only to the former and not the latter, perhaps the drugs would lack off-target activity.
Now, a new report reveals the design of a novel opioid that only works where inflammation exists, leaving healthy tissue untouched and avoiding the unwanted consequences seen with traditional drugs.
Using computer modeling, a team led by Christoph Stein, Charité – Freie Universität Berlin, and Marcus Weber, Zuse Institute Berlin, Germany, modified the chemical structure of fentanyl to create a new opioid, named NFEPP, that only binds to mu-opioid receptors (MORs) under acidic conditions, a hallmark of inflammation; this allowed them to target NFEPP only to sites of inflammation caused by tissue injury.
In two rat models of inflammatory pain, NFEPP was analgesic but did not lead to typical side effects such as sedation, addiction, and respiratory depression.
“It’s a very exciting development that you could have a mu-opioid receptor agonist that would be more preferential to the site of injury,”
“People have been working on biased opioid agonists that are tuned to one pathway over another, but this is a different angle in that it was designed as a pH-sensitive molecule.”
Location, location, location
The side effects of opioids, including nausea, constipation, addiction, sedation, and respiratory depression, are thought to occur because MORs are widely expressed throughout the body and brain.
As a result, researchers have sought ways to make opioids more specific to pain pathways while leaving non-pain pathways alone, through “biased agonist” approaches targeting mu-opioid receptors and kappa-opioid receptors, for instance (see PRF related news stories here and here).
This led Stein to consider the unique properties of injured tissue that could be exploited to target opioids to the desired areas. One such property is inflammation, which causes a drop in pH from physiological levels of 7.4 to acidic levels of about 5.4 (Holzer, 2009).
Co-first authors Viola Spahn and Giovanna Del Vecchio, along with Stein and colleagues, hypothesized that an opioid that binds MORs only during acidic conditions should activate the receptors only at sites of injury, where pain signals originate.
In the simulation, the investigators examined how a traditional opioid, fentanyl, interacted with MORs at different pH levels.
they settled on a design that replaced hydrogen atoms near the tertiary amine group of the fentanyl molecule that interacts with the MOR.
The next step was to actually synthesize the compound. They named it NFEPP.
From computer model to lab bench
As anticipated, fentanyl had similar binding affinities at both physiological and acidic pH. NFEPP, on the other hand, only had a binding affinity similar to that of fentanyl at acidic pH.
To demonstrate that NFEPP didn’t just bind MORs at acidic pH but also activated them, the team used an imaging technique called real-time fluorescence resonance energy transfer (FRET) to measure the dissociation of the three G protein subunits inside the cell that are bound to the MOR, an indication of functional MOR activation.
From lab bench to rodent
Knowing that NFEPP activated MORs only at acidic pH, the researchers then tested the drug in two rat models of inflammatory pain:
Intravenous fentanyl reduced this pain but also decreased sensitivity in the uninjured paw, demonstrating the non-specificity of fentanyl. NFEPP, however, relieved pain only in the injured paw. Not only did NFEPP avoid off-target activity, but it also produced analgesia comparable to the pain relief observed with fentanyl.
This new opioid would be useless for any pain that doesn’t also cause inflammation, like central sensitization. I wonder if there are other kinds of pain that are not associated with inflammation.
by only targeting MORs at the site of injury, NFEPP did not cause adverse side effects from off-target actions of opioids, including the addiction potential, respiratory depression, sedation, and constipation that were seen with fentanyl.
The long road ahead
Although very promising, NFEPP is years away from clinical use.
So, in the meantime, we should be allowed to use regular opioids.
ork,” said Nathaniel Jeske, University of Texas Health Science Center at San Antonio, US, who was not involved in the study. “My main concern is that they’ve identified an opioid that works in tissues that become acidotic, but opioids are used in many different types of pain where acidosis is not necessarily present.”
Reference: A nontoxic pain killer designed by modeling of pathological receptor conformations.
Spahn V, Del Vecchio G, Labuz D, Rodriguez-Gaztelumendi A, Massaly N, Temp J, Durmaz V, Sabri P, Reidelbach M, Machelska H, Weber M, Stein C
Science. 2017 Mar 03; 355(6328):966-969.