Itch and the Brain

As most of us know, a good scratch can satisfy an itch. Yet the question of why we itch and scratch in the first place has baffled researchers for years. Recently, however, science has begun to enlighten us to the mechanisms at work in the itch–scratch cycle.

For years, the itch sensation was thought to travel along the same nerve pathway used by pain signals. Itch, in fact, was considered a weakened form of pain. Modern molecular, genetic, and anatomical studies now indicate that itch usually follows its own distinct course, says Qiufu Ma, PhD, an HMS professor of neurobiology who has studied the phenomenon. Itch runs along a neuronal interstate highway system that links the skin, the spinal cord, and the brain.

Itch and pain represent different sensations that evoke distinct behaviors. Place your hand on a hot burner and you instantly pull it away; the pain is intense. By contrast, when a piece of clothing brushes against your bare forearm, you scratch to quiet the irritation, giving little thought to the sensation and your reaction to it.

“These distinct behaviors likely developed to protect us against different types of threats,” says

Anne Louise Oaklander, MD, PhD, an associate professor of neurology at HMS who studies chronic pain and itch. “Pain is obvious and, without it, we wouldn’t live long—there would be nothing to prevent us from putting our hand into a fire or onto that hot burner. ” She adds that the itch–scratch cycle most likely evolved to protect us from small, clinging threats—insects or plants—that can be avoided by withdrawal movements.

A scratch for every itch

Previously, few studies focused on the neural mechanisms associated with itch, but several recently have succeeded in identifying a neural component to the itch sensation and its scratch response. In 2009, neuroscientists at the University of Minnesota identified part of the mechanism by which scratch relieves an itch. They showed that relief takes place deep within the spinal cord along the spinothalamic tract. The STT transmits information about sensations, such as pain, temperature, touch—and, it turns out, itch—to the thalamus, deep within the brain. This relays the information to the brain’s center for perceptual awareness, the sensory cortex.

In their study, the researchers monitored spinal nerve activity in monkeys whose lower limbs had been exposed to itch-inducing histamine. With each exposure, the monkeys’ STT neurons went wild. But when the scientists used a device that mimics monkey fingers to scratch the itchy limbs, they saw a dramatic drop in STT neuronal activity. This sudden drop suggests that the act of scratching calmed the STT neurons.

In a recent study published in the journal Neuron, Ma identified a neural component necessary for the pain sensation and itch suppression that also may help answer the “why do we itch?” question. This component is VGLUT2-dependent synaptic glutamate, a molecule that is released from certain sensory neurons and that serves as a transport for glutamate, the most abundant neurotransmitter in the brain. Ma came across this pain–itch dualism unexpectedly, while monitoring the behavior of mice that had been genetically altered to lose the action of VGLUT2 in a group of peripheral sensory neurons. He discovered VGLUT2-deficient mice developed itch disorders as severe as those found in humans with chronic itch disorders. Essentially, Ma’s research team had created a mouse model that mimics some types of chronic itch in human patients.

“Removing VGLUT2 from pain-related sensory neurons in these mice weakened their responses to acute and chronic pain and caused the sensitization of multiple itch pathways,” says Ma. “The mice began to scratch until they developed skin lesions.”

The VGLUT2 pathway, says Ma, likely quells excessive itching by activating certain inhibitory neurons in the spinal cord or brain.

Insatiable itch

Common itches brought on by a chemical or mechanical stimulus—think mosquito bites and poison ivy—can be treated readily with agents that counteract histamine, a chemical the body produces to fight allergic reactions. A mosquito bite causes the body to release histamine in the area of the bite, turning the skin red and itchy. An antihistamine relieves the itch sensation by preventing histamine from binding to itch-instigating receptors in the skin.

Widespread itch, by contrast, is often caused by diseases of internal organs. More than 80 percent of chronic kidney disease patients have chronic, widespread itch, and some patients with liver disease and non-Hodgkin’s lymphoma also suffer from severe itch. Certain pain medications, such as opiates, can also trigger itching.

Neuropathic itch is a different kind of chronic itch caused by a malfunction of nerve cells. It appears in many of the same conditions that can cause chronic neuropathic pain, including shingles, a very common viral infection. The complications of shingles are a focus of study for Oaklander in her laboratory at the Nerve Injury Unit of Massachusetts General Hospital. Other conditions that can spur neuropathic itch include spinal cord lesions, brain tumors, and phantom limb syndrome.

“Neuropathic itch is ultimately caused by inappropriate firing of itch neurons in the central nervous system,” says Oaklander. “People with chronic itch often feel as if insects are crawling all over them.”

Few remedies are available for generalized or neuropathic itch. A new drug on the market, Remitch (nalfurafine), was developed to reduce itching in hemodialysis patients, and may also prove effective for other types of chronic itch that don’t respond to antihistamines. This treatment is based on paradoxical clinical observations: Morphine, which triggers a response in certain opioid receptors in the brain, suppresses pain but causes itch, while nalfurafine, which triggers action in another set of opioid receptors, suppresses itch. It is conceivable that a combination of morphine and nalfurafine might relieve pain without causing itch side effects. And, if scientists manage to develop compounds that activate the inhibitory pathway discovered by Ma and his colleagues, “we would have a completely novel strategy to treat itch,” he says.

“Scratching,” said the sixteenth-century French essayist Montaigne, “is one of the sweetest gratifications of nature and as ready at hand as any. But repentance follows too annoyingly close at its heels.”

Now that the scientific community’s view of itch has evolved to the point where it’s considered a bona fide and potentially serious clinical condition, people who suffer as Montaigne did—his eczema caused him to scratch incessantly—may finally find some relief.

This article appeared in the Summer 2011 issue of On The Brain.

Ann Marie Menting

For the curious nonscientist, On The Brain deciphers how the human brain works by highlighting the leading-edge research of neuroscientists at Harvard Medical School and its affiliated teaching hospitals. The thrice-annual newsletter, produced through the Office of Communications and External Relations, is sponsored by the Harvard Mahoney Neuroscience Institute.