The Mechanisms and Perception of Itch

When we feel an itch, we scratch it without thinking twice. But what causes itch in the first place? Why do we even have it? Our innate reaction to everyday itch is to scratch it, but in some skin diseases that cause chronic itch, scratching exacerbates the problem. Dr. Robert LaMotte, Professor of Anesthesiology and of Neurobiology at the Yale School of Medicine, conducts experiments on the perception and biological mechanisms of itch, using psychophysical and electrophysiological methods to measure the sensations of itch and responses of itch mediating sensory neurons.

The Biology Behind Itch

“Nociceptive” sensory neurons with small diameter nerve fibers are responsive to nox¬ious stimuli. A subset of nociceptive nerve fibers that terminate in the skin, respond to one or more chemicals that make us itch. These neurons are termed “pruriceptive” (from the latin word, prurere, “to itch”) whereas nociceptive neurons that do not respond to itchy chemicals are called “nociceptive specific.” Both types of neurons project to pathways in the central nervous system. So how does the brain decode itch from pain? LaMotte explained that the current thinking in the field is that activity in nociceptive specific neurons is interpreted by the brain as “pain,” whereas activity that occurs solely in the pruriceptive population is felt as “itch.”

A diagram of a neuron, the cell that transmits signals from the skin to the central nervous system. Image courtesy of Carleton University, Canada.

More than a decade ago, scientists in Germany found that histamine, a substance usually released during allergic reactions and causes itch, triggered activity in a specific type of nerve fiber terminating in the skin in humans. Most neurons that respond to histamine also respond to other types of stimuli, such as noxious heat, mechanical stimulation, or to capsaicin, which produces burning and stinging pain when injected into the skin.

Since the discovery of histamine’s connection to itch, research has elucidated a wide range of nociceptors, some nociceptive specific and others pruriceptive. Certain nociceptors respond to capsaicin and histamine; others respond to noxious heat and capsaicin but not histamine, and still others respond irregularly to mechanical stimuli, heat and histamine and to other itchy chemicals such as certain proteases. For example, one type of protease is contained in the hairs (spicules) of a tropical legume called cowhage (Mucuna pruriens). When these spicules fall off the pods of the plant their tips can stick into the outer layer of skin causing a prickly itch but without the release or presence of histamine. Because most types of clinically important itch are not relieved by anti-histamines, cowhage spicules have been useful in experiments that have identified a mechanosensitive, histamine independent pruriceptive neuronal pathway. Activity in these mechanosensitive neurons may explain why when patients with atopic eczema, a skin disease with chronic itching, put on wool sweaters, the mechanical rubbing of the wool against the skin causes itching. “We are trying to figure out how all the signals get sorted out in the central nervous system,” says LaMotte. “The goal is to identify the sensory neurons and pathways that mediate pain and itch, as they are very diverse and differ in many properties.”

Currently, there is no proven hypothesis on the functional basis of scratching the kind of transient itch we experience every day. One proposed idea suggests that since our skin serves a function of keeping fluids in and external irritants out, itchiness directs our attention to that area of our body so we can scratch and eliminate an irritant or parasite. “Parasites, though, can enter our body very quickly,” points out LaMotte, “So the chances of eliminating them by scratching are not very plausible.”

LaMotte proposes another possibility. Nerve endings are activated when our skin barrier is breached and a chemical irritant (for example from microorganisms living on the skin, activate pruriceptive nerve endings thereby resulting in itch and site-directed scratching. The scratching produces a minor “injury” that may trigger an inflammatory response that hastens the repair of the breach in the skin barrier.

A diagram depicting mast cells releasing histamine upon contact with an allergen, which causes itch and allergic reactions in the human body. Courtesy of MedlinePlus.

Skin Conditions with Chronic Itch

The skin condition eczema is the number one cause of itch. Over 18 million Americans suffer from the chronic, or atopic, form of eczema, and 20 percent of children in the Western hemisphere have chronic eczema. While most patients have a mild form of the condition, which is often treated with a topical steroid or moisturizer, around 10 percent of eczema patients suffer from severe itching.

What we commonly associate with itch, such as an insect bite, is merely temporary and bothersome. Most just react by scratching the itch, maybe even without thinking. The chronic itch of eczema, however, is a perpetual, irritating sensory perception that often results in much suffering. It induces a great urge to scratch, but scratching further damages the protective upper layers of the skin barrier. Damaged skin, stripped of its protective properties, causes nerve fibers just below the surface to be disturbed and overactivated, magnifying an even greater sensation of itch. Thus, scratching actually intensifies the perception of itch, thereby creating a painful and maddening itch-scratch cycle.

Itch in the LaMotte Lab

“Our long range goal is to identify the functional properties of different types of sensory neurons, specifically those mediating pain or itch,” explains LaMotte. “We pick a chemical stimulus that can produce itch in humans, ask human subjects to judge the magnitude of different qualities of sensations, like itch, pricking/stinging and burning, and apply the same stimuli to an animal model to analyze the responses of different types of sensory neurons and pathways.”

In his experiments, LaMotte employed the mouse as his model organism to investigate behavioral responses to itch and pain sensations. Steve Shimada, in the LaMotte lab, wanted to find out whether histamine (itchy to humans) or capsaicin (painful to humans) would evoke different behaviors when injected into the cheek of the mouse. It turned out that mice scratched the cheek with the hindlimb in response to histamine but wiped the cheek with the forelimb in response to capsaicin. A parallel dichotomy of behaviors occurred if the same chemicals were applied to the calf of the hindlimb. But in this case, histamine evoked more biting than licking whereas the reverse was true in response to capsaicin. LaMotte said “we concluded that the mouse model demonstrated a behavioral differentiation between chemicals that elicit itch and those that evoke pain.

Electrophysiology is then used to find the sensory neurons in the mouse that are transmitting the itch and pain signals. As LaMotte describes, “We record the nerve impulses activated by a particular chemical, which shows us which neurons are involved and whether this activity parallels the sensory behavior in mouse and in humans.” In collaboration with Chao Ma, a new physiological preparation was developed that allows the cell bodies of sensory neurons mediating pain and itch to be visualized in vivo. “The advantage of this approach is that individual neurons can be selected for optical imaging of cellular events or for electrophysiological recording,” LaMotte stated.

Ultimately, LaMotte says his goal is to get to know the cellular and molecular mechanisms that are special to each particular type of neuron. If specific neurons activated by itch stimuli are isolated, a targeted, sensory-specific drug might be developed to inhibit the transmission of the “itch.”

Tightly packed skin cells help create the natural barrier of the skin, while ingress of chemical solvents and water causes inflammation; Keratinocytes become less tightly held together.

Future Research for Itch

While current research focuses on periph¬eral sensory neurons, LaMotte hopes to identify cellular mechanisms specific to unique neurons and corresponding sensations. From a broader viewpoint, however, LaMotte says he strives to find out how sensations such as itch and pain are separately decoded in the central nervous system. For this, the mode of communication between distinct, unrelated nociceptors must be elucidated to show how sensory signals are deciphered. Once the neural pathways are identified, understanding of the mechanisms and perception of itch may pave way for potential future treatments.

About the Author
Jenny Mei is a sophomore in Berkeley College majoring in Molecular, Cellular, and Develop¬mental Biology. She is the Advertising Manager for Yale Scientific Magazine.

Jenny would like to thank Dr. LaMotte sincerely for his generous time and support, as well as an enlightening and intriguing discussion about his research involving the sensation of itch.

Further Reading
Chen, IngFei. “Digging Deeper to Understand Itch.” New York Times 25 April 2008: A11.
LaMotte RH, Shimada SG, Green BG, Zelterman D. “Pruritic and nociceptive sensations and dysesthesias from a spicule of cowhage.” J Neurophysiology. 101.3(2009):1430-43.
Shimada SG, LaMotte RH. Behavioral differentiation between itch and pain in mouse. Pain 139 (3), 681-687, 2008 PMID: 18789837.
Johanek LM, Meyer RA, Hartke T, Hobelmann G, Maine D, LaMotte RH, Ringkamp M. “Psychophysical and physiological evidence for separate neural pathways mediating histaminergic and non-histaminergic itch.” J Neuroscience. 27.28(2007):7490-7.
LaMotte RH, Shimada SG, Green BG, Zelterman D. “Pruritic and nociceptive sensations and dysesthesias from a spicule of cowhage.” J Neurophysiology. 101.3(2009):1430-43. ion