Doctors prescribe morphine with care. Patients quickly get used to the powerful painkiller, and ever higher doses are required to ease pain. Now, a paper in the 25 January issue of Cell shows that the onset of tolerance in rats can be slowed by giving the animals a small amount of a second painkiller.
Many painkillers induce tolerance by decreasing the number of so-called opiate receptors, proteins on the surface of neurons and other cells that snag the drugs. With most drugs, these receptors--and the drug bound to them--are pulled into the cell through a process called endocytosis. Some then recycle to the surface while others are destroyed. But morphine is different: The molecule stays on the surface, cradled in its receptor, and sends constant signals to the neuron.
So how does morphine induce tolerance? Cell biologist Jennifer Whistler and her colleagues at the University of California, San Francisco, decided to test the notion that cells with receptors stuck in the "on" position ignore the signal unless the dose is increased. If there was a way to switch off the signaling, the researchers reasoned--for instance by using endocytosis to periodically take the receptors out of commission--perhaps they could prevent tolerance.
The researchers dosed rats with a combination of morphine and a dash of DAMGO, an opiate that triggers endocytosis. They then measured the rats' morphine tolerance by testing the sensitivity of their tails to heat. All of the control rats on morphine noticed the warmth by day 7 and would flick their tails out of the uncomfortable heat, indicating that the morphine was starting to wear off. But rats drugged with DAMGO and morphine remained oblivious. Tests on spinal cord cells showed that 10 times as many opiate receptors in the DAMGO group had been pulled inside the neurons.
This is the first link between morphine tolerance and receptor endocytosis in live animals, says Brigitte Keiffer, who studies opiate receptors at the Louis Pasteur University in Illkirch, France. The work suggests that by adding a component such as DAMGO, researchers may be able to produce a painkiller that doesn't induce tolerance or dependence, she says.