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Toward Better Resolution of Pain

Media: The Inside Scoop

May 2010

Charles SerhanDr. Charles Serhan wears many research hats. He is the director of the Center for Experimental Therapeutics and Reperfusion Injury at Brigham and Women’s Hospital and the Simon Gelman Professor of Anaesthesia at Harvard Medical School. He also is an affiliate in Harvard Medical School’s Department of Biological Chemistry and Molecular Pharmacology and Professor of Oral Medicine Inflammation and Infection at the Harvard School of Dental Medicine. These titles have coalesced into a number of extremely productive research projects to elucidate the structure and function of endogenous bioactive small molecules, particularly those naturally involved in the resolution of inflammation. In the May 2010 issue of the journal Nature Medicine, Dr. Serhan and his colleagues report the latest wrinkle in his work on anti- inflammatory processes. The group shows for the first time in mice that certain resolution-inducing molecules called resolvins are extremely potent in controlling various aspects of pain in the central and peripheral nervous systems. Dr. Serhan, an NIDCR grantee, recently talked about the Nature Medicine paper and its potential implications.

All research has a story. How did you begin studying inflammation and resolvins?

It started in the 1980s. I was interested in how inflammation is regulated from its onset to its resolution. Does it follow a biochemical program that leads to chronic inflammation? Or are there biochemical prompts that tell the site to stop the inflammation and resolve? Those were the questions that drove us.

When you first posed these questions, the idea that biochemical prompts might actively resolve inflammation was a little like believing in the Easter bunny.

Well, that’s because the research then was almost completely focused on learning to control the initiation of the immune response. Resolution had fallen off of almost everybody’s radar screen. That led many to assume that, because initiation was so utterly complex and critical to the immune response, the back end must be a passive process. They figured the biochemical signals that activated the immune system simply dissipated on their own, like smoke filtering out of a room after a fire has been extinguished.

But you found that resolution isn’t passive at all.

That’s right. We found that if the initial stimulus is acute and not too harsh, our immune systems are programmed to return to homeostasis. In other words, acute inflammation is a protective response and its resolution is a tissue-programmed event that kicks in when the system is running properly. It allows the inflammatory site to drain, repair, and return to normal.

How is it programmed?

Biochemically. We discovered that there are signaling pathways wired into our cells that biosynthesize specialized lipid mediators that actively set in motion resolution. Just to review, lipid mediators are a broad group of naturally occurring small molecules that, in this case, are derived from fatty acids. In 1984, we identified the first class of pro-resolution compounds called lipoxins. In the early 2000s, we found the resolvins and protectins.

And, this paper in Nature Medicine involves the resolvins. What are they?

Think of them as messengers that spread the word chemically to resolve. They come in two unique chemical forms, called the D and E series. The D means the resolvin is biosynthesized from docosahexaenoic acid (DHA), and the E indicates that the resolvin is derived from eicosapentaenoic acid (EPA). Both DHA and EPA are omega-3 fatty acids. When most people hear this term, they think of news reports that eating salmon and other fatty fish is good for their health. But what these omega-3s actually do – their mechanism of action in the body – had been unknown. So our findings with DHA and EPA showed that they serve as the precursors from which inflammation-resolving molecules are made.

But how then did you move from resolvins in inflammation to their role in pain?

Pain and inflammation go together, especially in the periphery. This association led us a few years ago to look at the impact of anesthetics in resolution of inflammation. Do local anesthetics enable resolution to proceed? Or do they have a negative impact in resolution?

What did you find?

We found that some anesthetics actually delay resolution. They prevent scavenging immune cells called macrophages from cleaning up the debris after an inflammatory event. A few years ago, we started a wonderful collaboration on inflammatory pain here with Dr. Ru-Rong Ji, who is affiliated with the Brigham and Women’s Hospital Pain Research Center and is a senior author on the Nature Medicine paper. We thought the resolvins were pretty good candidates to improve resolution in inflammatory pain conditions. But before we could follow through on this idea a seemingly mundane technical advance was needed to allow the required mouse studies to proceed.

What was that?

We had to master how to inject the resolvins into the tight space that surrounds the spinal cord. Intrathecal injections, they’re called. In the mouse, the intrathecal space represents a really small target. But Dr. Ji and his group solved this, mastered the skill, and that’s how we ultimately sorted out in this paper that the resolvins can play a role in mediating pain within the central and peripheral nervous systems.

In reading the paper, you lined up the standard mouse models for various aspects of pain and established their potency one by one.

That’s right, we took a very systematic approach. The first panel is the standard pharmaceutical-level mouse model to evaluate compounds for their impacts to pain. The comparison here is between the resolvin E1 (RvE1), morphine, and the lead COX-2 inhibitor NS-398. The latter is an enzyme that catalyzes the formation of prostaglandins and other eicosanoids from arachidonic acid, and it’s known to be very good at reducing pain.

The results are pretty amazing.

We found that one nanogram of RvE1 had about the same effect as 100 nanograms of morphine. In other words, RvE1 is 100 times more potent than morphine and log orders better than NS-398. RvD1, one of the D series resolvins, also had a potent effect.

Did you think, “Something must be wrong here,” when you got your data?

Persistent effects of RvE1, NS-398 and 19-pf-RvE-1Of course. You always think that, especially when you get results like these that seemingly are so out there. But we systematically went through the data and got more mechanistic information. I think the result is as solid as you can get. If you jump to Figure 2, I think the most convincing experiment of all is found in Panel C. It lists RvE1 administered at three and 10 nanograms and the synthetic analogue 19-pf-RvE1 at 10 nanograms. The latter was created in the laboratory and has great potential as a lead compound for further analgesic testing.

Okay, I’m with you.

Well, when resolvins are produced during inflammation, they eventually are turned off as the system returns to homeostasis. What happens is an enzyme snips off one hydrogen group from RvE1, which changes its structure and makes it inactive. That’s not the case with 19-pf-RvE1, listed in red. This molecule blocks the removal of the hydrogen group, although it’s shaped the same as RvE1, and thus is longer acting. If you look at RvE1, in purple at six hours out, it has lost its action. But in red, the 19-pf-RvE1 analogue is still active. In addition, we found the regulation of leukocytes into the sites is dampened and all of the response-inducing chemotactic signals go down.

Meaning the conditions are ideal for resolution?

Exactly. The resolvins offer the added therapeutic benefit of stimulating resolution to clean up a damaged tissue.

Many pain medications are highly addictive. But would addiction be a concern for a compound derived from omega-3 fatty acids?

No. We still must forge ahead with the research to confirm this point. But no, I don’t anticipate addiction to be a problem.

Another really interesting finding in the paper is that the resolvins regulate the protein receptor called Trpv 1. That’s the receptor for capsaicin, the active component in chili peppers and one of the major targets for certain compounds to relieve pain.

Right. We had absolutely no idea this would be the case. Then Ru-Rong’s group forged ahead with the biochemistry and showed that resolvins block capsaicin-induced signaling events. It’s laid out in Figure 3. On a related note, we also found RvE1 had a different protein receptor than RvD1. As I mentioned earlier, the two are produced from different precursor molecules. So we’re reassured that the D and E series resolvins represent a non-redundant system, meaning they have different cellular targets that bring about a similar biological endpoint.

What about docsahexaenoic acid (DHA) or eicosapentaenoic acid (EPA), the precursor omega-3s. How do the resolvins compare with their chemical forebearers in potency?

It’s really quite interesting. RvE1 turns out to be far more potent than the precursors. Ru-Rong and his group found that you need something like 1,000 times more EPA and 10,000 times more DHA to get even a budge of an effect in hyperalgesia. And we eat milligrams of EPA and DHA at a time in oily fish. So, I think the resolvins will be very well tolerated therapeutically because they’re taken up by the body, probably by very similar mechanisms to those used for these essential fatty acids. Where the difference comes is the resolvins hit the G-coupled receptors on the surface of our cells, and that starts a cascade that amplifies getting back to homeostasis. So, the nutritional aspect of this is very interesting.

So, in a sense, through diet, a person can build up their capacity for resolution?

That’s a good way to put it. If you are well toned nutritionally with EPA and DHA – and this certainly remains speculative at this point – you would have a more timely pain resolution. But if you are deficient in EPA or DHA, pain resolution will be dealt with less efficiently. You’ll have more of a tendency to have persistent pain.

In other words, you could possibly control chronic pain through diet?

Right, let’s say I have a pain signal fire off. It’s supposed to dissipate in .5 milliseconds. If you’re in an optimal nutritional state, the sensation passes in .5 milliseconds. If not, you might have prolonged resolution of that pain signal and also the inflammation around it. I’m sure many other similar nutrient-related mechanisms exist in the body. This might be one of the first to be suggested at the structure/function level for pain and essential dietary fats.

What kind of doors does this open for further explanations?

I really want to focus on the internal, or endogenous, formation of resolvins and related compounds in our models of pain. That’s one thing that we don’t have in this paper. We wanted to lead with the information on the biosynthetic pathways because we thought it was very exciting. We plan to go deeper into how resolution occurs in nerve cells and the biochemical crosstalk involved. One of the things that we’re interested in is how immune cells called leukocytes talk to the neurons through chemical mediators.

So, the future looks really bright with this?

I think so. I’m hoping that we can really push this forward. To be able to move in parallel with human trials is really important, and I hope that will evolve. Once people start talking, then things happen.

Thanks for discussing the paper.

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This page last updated: February 26, 2014