BioEd Online

Here's a cool strategy for relieving pain: scientists have found that cold temperatures and even cool-sensation chemicals can be used to treat chronic pain.

Cold wet cloths and mint leaves pressed to the temple have long been used to put a damper on pain. But aside from the general numbing effect that ice can have on nerves, how cooling treatments work has remained a mystery. Now that the mechanism has been unpicked, researchers say, it could give new hope to sufferers of chronic pain, an often intractable condition affecting 50 million people in the United States alone.

Some nerve-ends in the skin are known to hold receptors that are sensitive to temperature changes as well as foods frequently described as hot (such as chilli) or cold (such as menthol). One of these receptors, called TRPM8, can help the body to monitor temperatures between about 8 and 12 °C, as well as being activated by menthol-like chemicals, including a super-cooling chemical called icilin.

Susan Fleetwood-Walker of the University of Edinburgh, UK, decided to investigate the link between these cold receptors and pain in rats. They first induced chronic pain in their animals by tying a thread around a thigh, and then either injected a very small dose of icilin into the spinal cord or had the rats stand in a shallow bath of the chemical. They then stroked the painful limb and checked the rats' response: those treated with icilin could withstand three times as much pressure. The findings are reported in Current Biology¹.

Cool relief

Activating the cold-sensing receptors sends a signal to the nerve's terminus in the spinal cord, where it then prevents other nerves from transmitting information about pain, says Fleetwood-Walker. "The terminals are actually touching pain-transmitting nerves and stopping them from being activated," she says.

The fact that the cooling message can block pain signals even those coming from elsewhere in the body wasn't known before. "If you just looked at the nerve itself you wouldn't know that it's having this gating control over all the other nerves," says Fleetwood-Walker. "It's only by looking in the whole animal that you can see this."

Similar work is being done at the other end of the temperature spectrum: earlier this year, Brian King and his team at University College London, UK, did some work on a similar receptor, TRPV1, which signals heat. They reported at a Physiological Society conference in July that heat can stop pain through similar blocking mechanisms. "We're just coming to realise that we can exploit this," he says. "There's potential at both ends of the temperature scale."

Throbbing pain

Fleetwood-Walker's team are hoping that their findings will translate to people suffering from chronic pain conditions such as arthritis, phantom-limb pain, or neuropathic pain, which can result when nerves are damaged through injury or disease. People with chronic pain show higher levels of TRPM8 receptors in nerves that are damaged, providing a target for these cool treatments.

The idea wouldn't work for acute pain, however, which operates through a different set of receptors.

The team recommends pursuing the idea of a chemically cool treatment, rather than, say, applying a cold cloth to the skin, because only a very specific temperature range would have the optimal effect on the TRPM8 receptors.

If the treatment works in people in the same way as it does in rats, it could cut out the side effects that plague many of the current treatments for chronic pain, such as morphine. And there will be no need to take tablets. "They could be applied directly to the skin in a cream or in a simple solution," says Fleetwood-Walker. She hopes to move into clinical trials within a year.

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