Drug allows morphine to relieve pain without addiction

A potential new treatment to prevent morphine addiction is at hand. Researchers have identified an immune receptor involved in addiction to the drug, and found a way to block this receptor without affecting pain relief. The discovery offers hope that morphine can be used to relieve pain without running the risk of addiction.

Opioid drugs such as morphine are known to target opioid receptors in the central nervous system, which block pain signals to the brain and flood it with the "feel-good" chemical dopamine. This reward response is what makes opioids so addictive.

Morphine is a widely used pain killer, but its addictiveness means it has to be administered with caution, and often cannot be used for protracted periods of chronic pain.

Mark Hutchinson from the University of Adelaide, Australia, and colleagues have now discovered that as well as working through the central nervous system, opioid drugs like heroin and morphine trigger an immune response, which seems to boost their addictive effects. Blocking this immune response in animals inhibits their addiction.

Hutchinson's team previously observed that opioids bind to TLR-4 ? immune system receptors in the cell membrane ? which are responsible for identifying foreign bodies. However, the team did not know how this binding affected the body.

Immunity receptor block

In their latest study, the team found that the receptor acts as an amplifier of reward when opioids are bound to it. The team did a series of experiments looking at addictive behaviour in rats and mice that had been given either morphine alone, or a drug called plus-naloxone ? which blocks the TLR-4 receptor ? followed by morphine.

Rats given plus-naloxone before receiving morphine did not exhibit behaviour linked to addiction. Their brains also showed a significantly lower release of dopamine than in rats that only received morphine. Using a heat sensitivity test, the team also showed that the rodents given plus-naloxone still experienced pain relief from the morphine, despite lacking signs of addiction.

To make sure that the TLR-4 receptor really was controlling these differences, the team also bred rats that lacked the receptor. Under the same tests, these rats behaved like those that had been given plus-naloxone.

The idea that the rewarding effect of opioid drugs is potentially mediated by this receptor "flies in the face of current opinion," says Chris Bailey, a pharmacologist from the University of Bath in the UK. "People for hundreds of years have been trying to come up with an opioid analgesic which isn't rewarding," he says.

These findings are particularly interesting, he says, because it's the first time a mechanism has been identified that separates the pain relief and reward responses to opioid drugs. "It has always been seen that the analgesia and the rewarding aspects go hand in hand," he says.

The next step will be to find out exactly how the receptor helps to control the reward behaviours linked to addiction, he adds. Clinical trials to test the effectiveness of combining morphine with a drug like plus-naloxone could begin as soon as 18 months from now.

Journal reference: Journal of Neuroscience, DOI: 10.1523/jneurosci.0684-12.2012

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