Reducing Tolerance To Morphine
Could Aid Pain Therapy

Morphine is one of the most commonly used drugs in the treatment of severe and chronic pain. A major complication with its use over the long term is that patients develop tolerance to it, as well as becoming addicted.

A way of reducing tolerance would be of great benefit, because it would allow doctors to use lower doses over longer periods and still control pain effectively.

A study published in this week's issue of Cell provides just that, by showing that giving a small level of a different drug at the same time as morphine can reduce the development of tolerance.

As well as highlighting an exciting new way in which morphine treatment could be improved, this study also gives important new insights into the overall mechanisms that lead to tolerance, and underlines a change in thinking that has been developing over the past few years.

Morphine acts by binding a receptor (the mu opioid receptor) on the surface of nerve cells and signaling from it. When this receptor binds to its normal signaling molecule, it is activated and then becomes desensitized.

The receptor then moves into the cell by a process called endocytosis. Once in the cell, it can then be reactivated and transferred back to the cell surface, ready to bind to a new signaling molecule and signal again.

Morphine, however, is not able to cause the desensitization and recycling, so morphine-bound receptors stay on the cell surface. Until quite recently, most researchers assumed that endocytosis of the receptors contributed to tolerance, because it would reduce the number of receptors available on the cell surface for binding to morphine.

However, recent studies have led to an alternative view, in which endocytosis might in fact help to reduce tolerance by recycling the receptors so they can become active again.

Jennifer Whistler and colleagues, working at the University of California in San Francisco, published results relating to this in Neuron in December 2001, where they showed that endocytosis is associated with reduced tolerance in cultured cells. In the new study, Dr. Whistler's group develop their findings and, most importantly, take the therapeutically important step of showing that they also hold true in whole animals.

In the new paper, Drs. He, Fong, von Zastrow and Whistler looked at clustering of the receptors into groups. Morphine-bound receptors can still cluster, but they do not normally move into the cell interior.

However, the authors found that binding of a compound called DAMGO to a small number of receptors in a group can cause the whole group to be taken up.

This means that a small amount of DAMGO can drag other receptors that have bound morphine inside the cells, ready for recycling. This caused a reduction in tolerance in cell culture assays, and receptor endocytosis in the spinal cord.

Most significantly, however, the authors found that over a seven day morphine treatment, giving rats a small amount of DAMGO at the same time as the morphine eliminated the tolerance that would normally develop during that time.

On the seventh day, the morphine dose was essentially as effective as it was on the first.

The significance of these results is clear: if we can develop a drug that will act in the same way as DAMGO to promote receptor endocytosis, this could be used with morphine to reduce tolerance, and thus increase the effectiveness of treatment.

Up to now, many drug discovery programs have thrown away candidate drugs that cause desensitization and endocytosis of morphine receptors, because they were working on the assumption that they would increase tolerance.

These new results show that, in fact, the opposite seems to be true, and give new hope for pain relief.

(Reference: Endocytosis of the Mu Opioid Receptor Reduces Tolerance And a Cellular Hallmark of Opiate Withdrawal, A.K. Finn and J. Whistler, Neuron Vol. No. 32 [2001] 829-839.)

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