Creams like BenGay can relieve minor aches and pains. But exactly why they work is a mystery. Now researchers have discovered a neurological mechanism behind such cooling remedies that, if tapped just right, could have implications for people with chronic and nerve-related pain.

A study published yesterday in the journal Current Biology reveals that activating a crucial protein in the skin may counteract the nerve signals associated with chronic pain brought on by nerve injury. One trigger for this protein receptor is menthol, an active ingredient in topical analgesics like BenGay. But an even more effective trigger is icilin – a chemical originally designed for toothpaste and nasal sprays. The researchers found that when applied to the skin, icilin stimulates the body’s natural cooling system, and helps block chronic, nerve-related pain.

“There’s a crying need to find safe painkillers for chronic pain use,” says Susan Fleetwood-Walker, a neuroscientist at the University of Edinburgh in Scotland and co-author of the study. “It’s extremely difficult to treat – and we never expected this cooling effect would have this huge effect that it does.”

Cooling remedies have been used for thousands of years. For instance, mint oil, which contains the cooling agent menthol, was a traditional Chinese salve. Products like BenGay are modern-day versions that act to cool irritation and inflammation. But such topical creams are more effective for acute pain – that is, pain resulting directly from tissue damage, such as a burn or pulled muscle. It’s much trickier to treat neuropathic, or nerve-related, pain, because the injured nerves themselves seem to generate pain signals without an external influence. Research into this type of chronic, nerve-related pain has focused on cutting off activation of pain neurons before signals reach the brain.

Much of the mystery of how this pain originates lies in the intricate mesh of sensory neurons underneath the skin. Different types of neurons detect different levels of temperature, pressure, and pain, sending this information to the spinal cord, and up into the brain. Within a particular set of temperature-sensitive neurons sits a protein receptor called TRPM8, which is wired to respond to cool yet not icy-cold temperatures. For example, a light breeze might activate this protein, sending an action potential along the sensory nerve into the spinal cord, which would then be relayed to the brain, producing a pleasant cooling sensation. Knowing this, the Edinburgh team looked for compounds that would specifically activate TRPM8, yet avoid setting off other more extreme sensory receptors.

The team experimented with low doses of icilin and menthol, respectively, on rats with clinically simulated chronic pain (an injured sciatic nerve). In separate trials, the rats were bathed in shallow pools of each solution, as well as injected with solution directly into the spinal cord. Researchers then tested the rats’ sensitivity to pain, noting when rats withdrew their paws in response to nylon filaments pressed against the injured leg. They found that after paddling for five minutes in icilin solution, rats experienced a marked decrease in pain sensitivity for up to five hours – a significant improvement compared with trials of menthol.

But the researchers didn’t stop there. Looking at electrical data from nerve firings in these rats, they discovered that the TRPM8 neurons, when activated, released a neurotransmitter, glutamate, into the spinal cord. And they found that glutamate released from cooling neurons turned around and inhibited signals from pain neurons. “What’s clever about this system and what nobody understood is…the TRPM8 sensory nerves are acting as a sort of control gate so the painful inputs don’t reach the brain,” says Fleetwood-Walker.

Observers say the findings are promising, albeit preliminary. “It is very unlikely that any one pathway or any one treatment is going to work on all types of pain, so instead we chip away at pain a little at a time,” says John T. Farrar, a chronic pain researcher at the University of Pennsylvania Medical Center in Philadelphia. “The animal model used in this study represents only one possible mechanism by which pain can occur in humans. However, it is clearly worth exploring – and perhaps we will get lucky with this one.”

The Edinburgh team plans to start human tests next year, experimenting with topical solutions of icilin on patients with nerve-related pain where treatments with morphine have been unsuccessful. The group is also looking for even more effective compounds than icilin as possible active ingredients for use in a topical cream that could one day provide cooling relief for people suffering from chronic pain.