Science has barely begun to scratch the surface of why an itch itches, and how to make it stop.
The itch-scratch cycle sits right at the fascinating intersection of pleasure and pain, reflex and compulsion, but it has received relatively little scientific attention. Ten years ago, one of the small band of international itch researchers called itch "sadly neglected," an "orphan symptom."
New developments are slowly beginning to refine scientific understanding of itch. They include the identification of nerve fibers devoted to transmitting itchy sensations, of brain sectors that process itch, and of molecules that seem to provoke itch. Itch experts hope that better treatments for itchy patients will soon follow.
People who sail through the occasional mosquito bite without a conscious thought may be unmoved by this news. But for the many others whose itch-scratch cycle has been deranged by yet-unknown neurochemicals into a tortured process that scars their skin, destroys their sleep and sometimes sends them to the brink of suicide, the dearth of scientific understanding and treatment options for itch is deeply frustrating.
"So many people suffer from itch," said Dr. Gil Yosipovitch, an associate professor of dermatology at Wake Forest University Baptist Medical Center in Winston-Salem, N.C., who has coordinated several international itch conferences. But financing for itch research is hard to come by, and effective treatment options for itchy patients are quite limited. "I do believe that our patients deserve better," Yosipovitch said.
Anyone doubting his word might pay a visit to Yosipovitch's Web site, www.itchforum.com, and watch five short video clips of patients with the itchy skin condition called atopic eczema. Filmed at night during sleep, the patients writhe in bed, unconsciously clawing at their faces, torsos, ankles and feet, clearly in the grips of a powerful primal instinct their doctors have been unable to interrupt.
Itch is a sensation that links the skin, the spinal cord and the brain in a kind of circular neural superhighway with exits all along the way. An itch may start anywhere along the loop _ or even in organs like the liver far removed from the loop _ and the process may then escalate into a vicious high-speed circular chase of itch and scratch, one worsening the other.
Sometimes, finding and treating a problem far afield from the skin itself is the only thing that can stop the cycle.
The simple mosquito bite is one of the few causes of itch that scientists feel they understand fairly well, and even it is full of unknowns.
When a mosquito injects its saliva into the skin, antibodies against molecules in the saliva cause cells in the skin to release the well-known itch mediator histamine. Histamine causes nerves in the skin to send an alarm up the spinal cord to the brain.
The precise path of that signal, and what happens when the alarm reaches the brain, is still full of conjecture.
Until recently, researchers thought that feelings of itch traveled to the brain along the same nerves as feelings of pain, and that, in fact, itch was really just an attenuated form of pain.
But many researchers felt that this assumption had to be wrong. How could itch and pain share nerves, they reasoned, when, among other differences, the two sensations are completely different, and elicit very different responses? Pain provokes instant withdrawal from the source of the pain, while an itch provokes a scratch. Sure enough, in 1997 a group of German physiologists identified a family of tiny slow-conducting nerves with broad tentacles in the skin that seem to be devoted to itch alone.
"The discovery of a specific itch pathway caused a cataclysmic shift in thinking about itch," said Dr. Earl Carstens, a professor of neurobiology at the University of California at Davis. This new finding emphasizes that itch is a unique sensation that requires specific research of its own.
Meanwhile, events in the brain segment of the itch pathway are also newly unfolding.
Several years ago, researchers injected tiny quantities of histamine under the skin of volunteers _ effectively giving them artificial mosquito bites _ then scanned their brains with positron emission tomography, or PET technology, which displays activated areas.
As the volunteers' skin began to itch, their brains showed intense activity in sectors responsible for sensation, sectors responsible for planning and initiating movement and also in deeper areas of the brain where the more primitive emotions of pain and pleasure are processed.
In other words, the brain has no specific "itch center," the researchers concluded. Rather, itch seems to be a multidimensional neurologic web incorporating sensation and action along with deeper emotional overtones.
If itch is a mystery, scratch is even more so.
In its basic, most primitive form, scratching is a reflex that is controlled by the spinal cord and requires no input from the brain. Experimental animals whose spinal cords have been severed from their brains still have a scratch reflex. But the action of scratching a specific, annoying itch requires the brain to supply the strategy, strength and coordination to supplement the primitive spinal reflex.
"The big mystery in the field is the link between the itch pathway and the scratch reflex pathway," Carstens said.
Even the basic question of why a scratch relieves an itch is still not definitively answered.
The general theory is that scratch provides a counterirritation: a slight pain that functions as a kind of transient neurologic distraction for the brain. Focusing on the discomfort of the scratch, the brain eventually forgets the itch.
Sometimes, though, scratching itself may provoke more itching, Yosipovitch said, possibly through damage to the upper layers of the skin, which release yet unidentified molecules that then bring on the sensation of itch again.
Meanwhile, the relationship between pain and itch has still further complications.
Powerful painkillers like morphine are notorious for provoking itching, especially if they are injected directly into the fluid that bathes the brain and the spinal cord.
The explanation for this observation: Because the sensation of pain seems to be essential to the process of quelling itch, when the ability to feel pain is dampened by morphine and similar drugs, intractable itch may result. There is evidence that natural morphinelike molecules in the brain, called opioids, may also play an important role in producing the sensation of itch.
Even though doctors do not yet entirely understand this phenomenon, they have begun to harness it for the treatment of some kinds of chronic itch that have no other known treatments.
Only a few kinds of itch can be relieved with antihistamine drugs like Benadryl (diphenhydramine) because only a few, like mosquito bites and allergic skin reactions, are caused by histamine release in the skin. Most other itchy skin conditions _ among them dry skin, eczema, fungal infections and psoriasis _ do not appear to involve histamine, and thus are seldom relieved by antihistamines.
Instead, these itches sometimes respond to antibiotic creams, skin moisturizers or drugs that suppress the immune system like steroids.
But itching complicates other medical conditions too: It is very common in people with certain kinds of liver disease and also in people with kidney failure even after they go on dialysis. Frequently, no treatment is successful.
For these itchy people, antihistamine drugs do not work well _ and creams and ointments do not work either.
In 2001, two British liver specialists described in a European medical journal the case of a woman with liver disease who was so miserable from intractable itching that she almost received a liver transplant.
Studies have shown, however, that intractably itchy patients like her can sometimes be helped with drugs that counteract the effects of morphine.
These drugs work by blocking opioid receptors in the body's cells, and are often used to treat people with drug overdoses. The fact that opioid antagonist drugs relieve itch that nothing else helps has suggested to scientists that in some patients itch may be caused at least in part by too many natural opioid molecules circulating in the brain.
Instead of a liver transplant, the British woman was treated with the opioid blocking drugs naloxone and naltrexone. Her itch subsided completely, and she avoided life-threatening surgery.
But itching and scratching are not always dire medical problems. They can also provide pure pleasure, as anyone who has ever wielded a back scratcher in just the right spot knows well.
"No one has figured out why it is so pleasurable to scratch an itch," Yosipovitch said.