Source: Nature
Date: 11 May 2000

Dial 'P' for pleasure

A new way to beat morphine addiction could be in prospect
thanks to work on genetically engineered mice.


There is a chemical in the brain with an enigmatic name that seems to be involved in a variety of emotional responses. Modulating the activity of this substance has been suggested as a radical new way of dulling anxiety, relieving depression and beating stress.

This mystery molecule is involved in the perception of both pleasure and pain. Now research reported in Nature1 shows that it has a specific part to play in the brain's response to opiates -- substances including drugs of abuse such as morphine and heroin. The name of this chemical -- simply, 'substance P' -- could come straight out of a James Bond movie.

Stephen P. Hunt of University College, London, and colleagues have been studying the behaviour of mice specially bred to lack the gene for the receptor for substance P. Without this receptor -- known as the 'Neurokinin-1' or 'NK-1' receptor -- substance P cannot work, and all sorts of interesting things happen.

In 1998, the researchers showed that mice without the NK-1 receptor were less responsive than normal mice to pain. This is not to say that the mice felt no pain, but they did not show the usual reflexes or behaviour associated with pain, such as stress. Nor did they show the normal aggressive response to territorial challenge.

If these results are translated to humans, it could be that the aura and associations of fear surrounding pain -- rather than pain itself -- involve substance P. So therapeutic intervention in the relationship between substance P and its receptor might be useful in combating emotional problems such as stress or anxiety. One consequence of stress in some people is to fall back on bad but comforting habits, such as eating or drinking -- and taking hard drugs.

Substance P is found both in parts of the brain linked to the processing of responses perceived as depression, anxiety and stress, and in a brain region called the nucleus accumbens. This area is associated with the motivational properties of natural rewards (such as food) and drugs of abuse, including opiates. If we need a little help from heroin or just chocolate, we feel it in the nucleus accumbens.

In their latest research, Hunt and his collaborators show that mice without the NK-1 receptor are unresponsive to substance P and do not experience the pleasurable effects of morphine. Similarly, they do not experience the physical effects -- 'cold turkey' -- of morphine withdrawal.

Mice without the NK-1 receptor did get a kick from cocaine because cocaine works through a different set of neural pathways from those controlled by substance P.

This research looks promising for the treatment of addiction in humans. A drug that dulls the activities of the NK-1 receptor could be used to wean addicts off opiates and keep them off. And if the link between substance P and stress holds up, it could also be used to dampen the craving for drugs when times are hard.

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