The drain pain. Morphine causes of opioid receptors to stick on the surface of these cells (left); a small dose of a second analgesic stimulated uptake receptor -. that, in rats, tolerance prevented morphine (right)
Doctors prescribe morphine carefully. Patients quickly used to the powerful painkiller, and increasingly higher doses are needed to relieve pain. Now an article in the January 25 issue of cell shows that the development of tolerance in rats can be slowed by giving the animals a small amount of a second painkiller.
Many analgesics induce tolerance by decreasing the number of so-called opioid receptors, proteins on the surface of neurons and other cells that cling to the drug. With most drugs, these receptors - and the drug bound to them - are drawn into the cell through a process known as endocytosis. Some then recycled to the surface while others are destroyed. But morphine is different: The molecule remains on the surface, cradled in its receptor, and sends constant signals to the neuron
So how morphine induced tolerance.? Cell biologist Jennifer Whistler and colleagues at the University of California, San Francisco, decided to test the idea that cells with receptors stuck in the "on" position to ignore the signal unless the dose is increased. If there was a way to disable signaling, motivated researchers - eg using endocytosis periodically take the receivers out of commission. - Maybe they could prevent tolerance
The researchers dosed rats with a combination of morphine and a pinch of DAMGO, an opiate that triggers endocytosis. They then measured the morphine tolerance in rats by testing the sensitivity of their heat tails. All control rats on morphine noticed the heat by day 7 and would flick their tails out of the uncomfortable heat, indicating that the morphine was beginning to dissipate. But rats drugged with morphine and DAMGO remained unconscious. Tests on cells of the spinal cord showed that 10 times more opioid receptors in the group DAMGO were pulled inside neurons.
This is the first link between morphine tolerance and endocytosis receptors in living animals, says Brigitte Keiffer, studying the opiate receptors in the Louis Pasteur University in Illkirch, France. The work suggests that the addition of a component such DAMGO, researchers might be able to produce an analgesic that does not induce tolerance or dependence, she says.
Greene, Katie
Related Sites
homepage Jennifer L. Whistler
A page on the receptor mediated endocytosis
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