Manipulating a matrix of pain

Molecules that bind skin cells together influence the transmission of pain

“Where does it hurt?” a doctor says, and it sounds like a simple question; a patient is supposed to point to the offending region of the body. But a look at the details of how sensations arise reveals that the question isn’t so straightforward: pain begins with a response from nerves near the site of an injury. For the brain to perceive it, those neurons must generate electrical impulses that travel to other nerves in the spinal column and on to the brain. The impulse – and the sensations it causes – can be blocked at many places along the way. Now Gary Lewin’s group at the MDC has discovered that some signals are interrupted right at the source. A matrix of proteins that bind cells together in the skin can interfere with the contact between neurons and dampen touch sensation. Without this mechanism, people suffer from severe pain in a condition called epidermolysis bullosa, sometimes termed butterfly disease. The lab’s findings, published in the July 3 issue of Nature Neuroscience, reveal that a matrix protein called laminin-332 helps tune down sensations of pain and touch.

The skin needs to be tightly sealed to protect the body from water and dangerous substances in the environment. The seal consists of a dense matrix of glue-like proteins that stick cells to each other, including laminin-332. Sensory nerves end in the extracellular space in the skin and are surrounded by the same glue-like matrix of proteins. Brushing or probing the skin leads to an electrical excitation of these endings in their matrix-glue.

Normally, proteins in the matrix are required for an efficient transfer of the stress and strain produced by skin movement to the sensory endings in the matrix. The Lewin group has found that one component of the matrix normally acts to dampen down or inhibit the mechanical activation of the sensory endings in the skin. Laminin-332 was identified by two scientists in the Lewin lab, Li-Yang Chiang and Kate Poole, as a protein which naturally brakes the initiation of sensory signals that lead to pain. In human patients who lack this protein, the same sensory endings can be activated by normal stroking and probing of the skin, thereby amplifying pain.

As nerves grow, their tips branch many times to establish contact with other cells. If the endings of sensory branch excessively, the result will be amplified response to touch and pressure. The scientists also discovered that the presence of laminin-332 helps prevent too much branching in the skin.

The skin is made up of layers consisting of several types of cells, each of which is bound to its neighbors in different ways. This creates environments that develop different types of nerve architecture. One goal of the recent work was to show how the differences affect the transmission of sensory information.

“Pain-detecting nociceptors extend to the surface of the skin, into the layer called the epidermis,” Gary says. “Mechanosensory cells that detect touch reside exclusively in a lower layer, the dermis. Li-Yang and Kate found that laminin-332 blocks or lowers transmission from the nociceptor cells as they extend into the epidermis.”

In other words, if the keratinocyte cells that make up the dermis lack a working version of laminin-332, more nerves will be stimulated and will transmit stronger signals.

“People who suffer from epidermolysis bullosa don’t have laminin-332 – or they have a version of the molecule that doesn’t function well,” Gary says. “This work offers a mechanistic explanation for the intense pain that they experience.”

– Russ Hodge

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