By Scicurious | August 15, 2012

Or not.

I so want to like press releases. But I got this press release:


And I got the paper along with it. As I read the paper, my head slowly hit the desk. And hit it again, and again, as I compared the press release to the paper and prepared to write this post. I will have a lovely little round bruise now.

But let’s get the big questions out of the way first:
1. Is this paper good? Oh yes! Really neat! Cool new mechanism!
2. Does it “block” heroin addiction? No.

This press release hurts us precious. It hurts us. I’m going to let it speak for itself:

Scientists can now block heroin, morphine addiction

In a major breakthrough, an international team of scientists has proven that addiction to morphine and heroin can
be blocked, while at the same time increasing pain relief.

The team from the University of Adelaide and University of Colorado has discovered the key mechanism in the
body’s immune system that amplifies addiction to opioid drugs.

Laboratory studies have shown that the drug (+)-naloxone (pronounced: PLUS nal-OX-own) will selectively block
the immune-addiction response.

The results – which could eventually lead to new co-formulated drugs that assist patients with severe pain, as well
as helping heroin users to kick the habit – will be published tomorrow in the Journal of Neuroscience.

“Our studies have shown conclusively that we can block addiction via the immune system of the brain, without
targeting the brain’s wiring,” says the lead author of the study, Dr Mark Hutchinson, ARC Research Fellow in the
University of Adelaide’s School of Medical Sciences.

“Both the central nervous system and the immune system play important roles in creating addiction, but our studies
have shown we only need to block the immune response in the brain to prevent cravings for opioid drugs.”

The team has focused its research efforts on the immune receptor known as Toll-Like receptor 4 (TLR4).

“Opioid drugs such as morphine and heroin bind to TLR4 in a similar way to the normal immune response to
bacteria. The problem is that TLR4 then acts as an amplifier for addiction,” Dr Hutchinson says.

“The drug (+)-naloxone automatically shuts down the addiction. It shuts down the need to take opioids, it cuts out
behaviours associated with addiction, and the neurochemistry in the brain changes – dopamine, which is the
chemical important for providing that sense of ‘reward’ from the drug, is no longer produced.”

Senior author Professor Linda Watkins, from the Center for Neuroscience at the University of Colorado Boulder,
says: “This work fundamentally changes what we understand about opioids, reward and addiction. We’ve
suspected for some years that TLR4 may be the key to blocking opioid addiction, but now we have the proof.

“The drug that we’ve used to block addiction, (+)-naloxone, is a non-opioid mirror image drug that was created by
Dr Kenner Rice in the 1970s. We believe this will prove extremely useful as a co-formulated drug with morphine,
so that patients who require relief for severe pain will not become addicted but still receive pain relief . This has the
potential to lead to major advances in patient and palliative care,” Professor Watkins says.

The researchers say clinical trials may be possible within the next 18 months.

This study has been funded by the National Institute on Drug Abuse (NIDA) in the United States and the Australian
Research Council (ARC).

This paper has a lot of GREAT things about it, and there’s a lot of potential for the future with a new mechanism for drug action, especially in the area of pain relief (which sadly got short shrift in the press release). But no one has cured addiction yet.

And this press release is downright vague, to say the least. “Avoiding the wiring?” What the heck does THAT mean?! No matter what you do in the brain, I assure you there’s no “avoiding the wiring”.

But this paper is a good paper. And it’s not that complicated! So I’m going to take you through it, and we’re going to talk about the implications. And then we’ll be able to see what’s been cured, what’s been hyped, and where the possibilities lie.

Hutchinson et al. “Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement” Journal of Neuroscience, 2012.

(This is not (+)-naloxone, the drug they studied. Instead, it is remifentanil, one of the drugs they blocked the effects of, but the drug is here binding to the MD2 receptor complex involved with toll-like receptor 4)

Let’s start with a brief description of how opiates are thought to work. Opiates, including drugs like morphine, heroin, and oxycodone, are drugs that act via the receptors of your (aptly named) endogenous opioid system. When activated, the receptors of this system (the most famous being the mu-opioid receptor) reduce pain. Activation of these receptors will also indirectly increase dopamine in reward-related areas of the brain, resulting in the highs associated with opiate use (opiate receptors are also in other areas of the body, so there are side effects including some fun ones in your gastrointestinal tract). So opiates are highly addictive drugs, producing long lasting and tough addictions to treat. Treatments include things like naloxone, an inverse agonist of the opioid receptors which can reverse overdoses, and drugs like methadone, which are long and slow acting drugs that replace the morphine and heroin and allow someone to function without being high.

But. Opiates are also the most effective pain medications available. There really is nothing else that compares. So scientists are constantly looking for ways to develop new opiate drugs that could relieve pain, but without the addictive side effects. And of course we’re always looking for new drugs to treat addiction.

This team of scientists in particular is looking at (+)-naloxone. If the name sounds familiar, that’s because (+)-naloxone is a synthetic mirror isomer of naloxone. Naloxone (Narcan) is the opioid inverse agonist that can counter an opiate overdose. (+)-naloxone is an isomer of it, and so blocks opiate receptors. This has some nice effects on the drug-addiction-related effects of opiates.

What you can see above is a paradigm called conditioned place preference. This is thought to assess drug reward in animals. You put a rat, say, in a box. The box has two chambers on either side. First you put him in one chamber, and before you put him in, you inject him with morphine. Sweeeet. Then, you put him in the other chamber, an inject him with saline first. If you repeat these pairings for several days, the animal learns to associate one compartment with the drug. Then put him in with no drug, and see which side he prefers. If the drug you are testing is, say, morphine and highly rewarding, he will prefer the morphine-paired side. If not, he will show no preference, or even prefer the saline paired side if the drug you are testing is aversive.

So this graph above shows morphine conditioned place preference on the top (black bars), as compared to saline (clear bars). Then they co-administered the morphine with their (+)-naloxone. You can see that the co-administration with the (+)-naloxone blocked the place preference for morphine, blocking the rewarding effects of morphine in this test.

And it’s not just morphine. What you can see here is drug self-administration. You place a rat with a i.v. catheter into a box with a lever. When it presses the lever, it receives a shot of drug, in this case the fast acting remifentanil, i.v. As you can imagine this feels pretty good, and the rat is soon pressing quickly (as you can see from the clear circles and squares). But when the rats get (+)-naloxone immediately before their self-administration session, they fail to self-administer the drug. So it looks like (+)-naloxone blocks the self-administration, or the rewarding and reinforcing effects of the drug.

They also looked at dopamine levels in the nucleus accumbens, an area associated with the addictive properties of drugs. Normally, opiates increase dopamine release in this area, but in this case, giving (+)-naloxone with morphine blocked the increase in dopamine.

This is some pretty interesting stuff. But it doesn’t actually mean that they “blocked addiction”. They blocked the effects of the drugs, but these rats were not addicts, and they did not look at things like reinstatement for drug-seeking behavior or other measures. (+)-naloxone clearly blocks the rewarding and reinforcing effects of the drugs, but there’s a big difference between blocking the effects in a rat that’s only had a few days experience, and blocking them in a years-long addict. Reward related systems change very drastically after long-term exposure to drugs like morphine or heroin, and remember, this has not been tested in humans. No human has tried it and gone off heroin forever. I definitely think they should test it, but it hasn’t “blocked addiction” yet. There are plenty of other drugs that “block” drug self-administration and conditioned place preference for drugs like cocaine and yes, morphine. But they haven’t been successfully translated to patients.

But that’s just the beginning. There’s a lot more to this study, and this is where all the really interesting mechanisms begin. Let’s get it started.

Now we move on from opiates to the interactions between the drugs that enter your body and your immune system. The immune system has begun to receive a lot more attention in the neuroscience world lately, from depression to addiction. These authors were interested in toll-like receptor 4. Toll-like receptors are receptors that respond to things that are foreign to the body. Toll-like receptor 4 is specific to the central nervous system, where it plays a very important role. Getting a cold is one thing, but getting a bacterium or other foreign thing in your CNS is quite another. So we have receptors like toll-like receptor 4 which identify foreign things, including DRUGS, in the CNS. They can then provoke an inflammatory response using a pathway known at the MyD88-dependent pathway.

And it turns out that one of the classes of drugs that activate toll-like receptor 4 and its pathway are the opiates. Conversely (+)-naloxone blocks toll-like receptor 4. But the question is, what does this do?

To examine this, the authors of the study used mice that were knockouts for toll-like receptor 4 or MyD88.

What you can see above is another conditioned place preference experiment, this time with oxycodone (why they switched opiates in between all of the experiments, I don’t know, using the same one would be more consistent, but probably, given the number of collaborators, these experiments were done at different times and places). You can see that oxycodone produces place preference in normal mice, but that in the knockouts for toll-like receptor 4 and MyD88 (the two right sets of bars), there was no place preference. So it looks like activation of this immune-related receptor may be required for opiate place preference, which is pretty drastic. It suggests that the toll-like receptor 4 could be a good target on its own to help deal with drug addiction, without having to target the opiate system, though a lot more research is going to be required to determine that. But it’s a really interesting new mechanism, and one very worth pursuing.

But there’s one other thing we forgot: pain relief. After all, if (+)-naloxone blocks the rewarding effects of opiates…it probably doesn’t help pain, right?

WRONG! Not only does (+)-naloxone not hinder pain relief, it appears to even potentiate the effects. What you can see above is a pain test in mice, tail withdrawal latency from a hot plate. You put the mouse’s tail on the hot place, and see how long it takes for the mouse to move its tail away. When you add a pain reliever like remifentanil, the mouse takes longer to move its tail away because it can’t feel the pain. In this case, (+)-naloxone actually increased the analgesic (pain-killing) effects of remifentanil!

What is the mechanism?

The mechanism appears to be toll-like receptor 4. When they did a potency assay for oxycodone in normal mice and knockouts for toll-like receptor 4, they found that toll-like receptor 4 knockouts were more sensitive to the oxycodone.

So not only could toll-like receptor 4 have effects in the rewarding properties of opiates, it could help to potentiate pain relief.

It’s a good study, and the implications are there for both the addition-related findings and the pain, but I actually think the press-release took the wrong tack, here. (+)-naloxone has not cured addiction. But it could do great things with pain. Because it appears to have no addictive properties itself (it produces no place preference, but I would like to make sure its not self-administered, though I don’t think it would be), but it potentiates the pain relief from opiates, it could be given as a combination medication with traditional opiate painkillers. This means that we could use much lower doses of opiates than we current do, and use (+)-naloxone to make up the difference, hopefully reducing the possibility of people becoming addicted to their painkillers.

This is HUGE. There have been very few recent breakthroughs in pain pharmacology, and a drug like this has a lot of potential.

And the addition of toll-like receptor 4 is a nice new mechanism, it’s nice to see the new immune focus bear interesting fruit. I would be glad to see drugs targeting this receptor get tested and see what they might do on their own.

My question is, why did the press release focus on the drug addiction? While the drug addiction angle is interesting, the pain angle seems to have more immediate therapeutic use. I suppose heroin is always sexier than pain. But keep in mind: this paper is really interesting. There’s a lot of good stuff here, some new mechanisms and new therapeutic angles. But we haven’t “blocked addiction” yet.

M. R. Hutchinson,1,4* A. L. Northcutt,1* T. Hiranita,7 X. Wang,1,3 S. S. Lewis,1 J. Thomas,5 K. van Steeg,4,6 T. A. Kopajtic,7 L. C. Loram,1 C. Sfregola,1 E. Galer,1 N. E. Miles,1 S. T. Bland,8 J. Amat,1 R. R. Rozeske,1 T. Maslanik,2 T. R. Chapman,1 K. A. (2012). Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement Journal of Neuroscience, 32 (33)

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