Why Do We Itch?
Do you ever come across an article or a title that catches your attention and drives you to learn more?
Well, this just happened to me. I was looking for some interesting science to write about when I came across a journal article titled “Neural Mechanisms of Itch” in the current volume of the Annual Review of Neuroscience. I, like you, experience itches and the need to scratch, but I’ve never thought about the biology behind these sensations. Being a science nerd, I needed to learn more. As is often the case in biology, it turns out that this mundane sensation is actually associated with a complex series of biological processes.
Humans, as well as a host of species up and down the evolutionary ladder, experience the urge to scratch. This urge is called pruritus – or more commonly – itch. The feeling of itch normally begins in the peripheral nervous system with a type of neuron called a pruriceptor. These cells are closely related to the neurons that detect pain and recent genetic work has helped better identify and categorize the pruriceptors as researchers work to better understand why we itch.
Molecularly, itch stems from the activation of specific classes of receptors on cells: G protein-coupled receptors (GPCRs), cytokine/chemokine receptors, and cellular ion channels.
GPCRs are a huge family of receptors that bind to a variety of molecules – their respective ligands. The best-known example of a GPCR/ligand signaling axis in the itch field involves histamine, which is frequently associated with allergic reactions. In the context of itch, histamine binds to the H1 receptor and H4 receptor, two histamine-specific GPCRs. Common antihistamine medications target the H1 receptor to alleviate itchy symptoms. Certain GPCRs can also induce itch by binding to specific proteins and peptides. Activation of some of these receptors has been associated with chronic itch. More recently other GPCRs have been associated with itch signaling. These receptors are responsible for binding to bile acid and bilirubin, components of bile. While the underlying biology is still unclear, these findings may potentially explain the itchy feeling that’s often felt by patients with liver disease.
In addition to GPCRs, receptors that bind to cytokines and chemokines play important roles in itch sensation. Cytokines and chemokines, as mentioned in other posts, play important roles in regulating the immune system. In itch research, these receptors appear to be responsible for chronic itch conditions. A cytokine called IL-31 is the most well-known cytokine involved in itch signaling. This cytokine is secreted by T cells, an immune cell type, and has been associated with dermatitis. Inhibiting IL-31 in preclinical studies reduces dermatitis and blocks the itch normally associated with this cytokine. Other cytokines associated with itch include IL-33, IL-4, and IL-13. IL-33 is thought to be involved in the itch that stems from touching poison ivy, while IL-4 and IL-13 bind to receptors on neurons to help enhance the itch from other stimuli. The relationship between the immune cell-produced cytokines and their respective receptors on neurons is another example of the neuro-immune relationship.
A third class of signaling associated with itch stems from ion channels. Ion channels are pores in the cell membrane that normally bind and transport ions – like sodium, calcium, and potassium – in and out of cells. Two sodium ion channels, Nav1.9 and Nav1.7, have been shown to contribute to itch signaling. Interestingly, the ion channel Trpv1, the receptor that binds to capsaicin from chili peppers, has been implicated in itch signaling through the binding of specific lipid molecules, and this role is thought to be associated with histamine-driven H1 receptor signaling.
As you can see, there are key interactions between receptors and their ligands during the propagation of the itch signal. But where do these itch ligands come from? The stimuli for itch are believed to originate from several sources, including immune cells and keratinocytes (skin cells), as well as external factors like insects. While some itch-related stimuli can come from T cells, the main immune cell source for itch initiators are mast cells. These cells release the itch-inducing histamine, as well as IL-4 and a variety of other compounds that can bind to itch receptors on neurons. Similarly, basophils, which are immune cells that can also readily release histamine and other inflammatory factors, have also been linked to itch propagation. Histamine can also be released by keratinocytes under certain conditions, though in smaller quantities than produced by mast cells. Keratinocytes can also produce other itch-related compounds, including factors called endothelin-1 and TSLP. Keratinocytes can also recruit mast cells to the skin to propagate itch signaling. This process has been associated with the itch observed in certain types of dermatitis.
In addition to the chemical stimuli for itch, there are also mechanical stimuli that trigger itch sensations. The itch response to mechanical stimuli may have evolved out of a need to detect and repel potentially dangerous insects and parasites from the skin. The presence of a parasite on the skin causes a slight deformation of the skin or movement of a hair, and this mechanical change is sensed as an itchy feeling by the host. If you’ve felt the need to scratch your arm when a fly landed on it or scratch your foot as an ant walked across it, you’ve experienced this signaling process. Interestingly, mechanically induced itch may involve a different signaling chain than the chemically induced itch seen with histamine release. Mechanically induced itch is thought to involve the spinal nervous system, including neurons that express neuropeptide Y (Npy), though the process is less understood than chemically induced itch.
It turns out that the spinal cord has important roles in regulating itch signaling. Neurons in the spinal cord express multiple receptors associated with propagating itch sensations, but it is also involved in turning off the itchy feeling through the transmission of counterstimuli. Researchers have found that activation of spinal neurons involved in sensing and transmitting heat, cold, and pain is able to inhibit histamine-induced itch. This may help explain why scratching or putting a hot/cold compress on an itch can help alleviate the itchy feeling.
Complementing the role of the spinal cord, the itch signals are also carried to the brain. Within the brain, the parabrachial nucleus (PBN), the periaqueductal gray (PAG), and thalamus regions have been shown to be critical for itch sensation. Researchers have also used MRI imaging to demonstrate that itch sensations lead to increased blood oxygen levels throughout the brain’s cortex, and current work is delving into understanding the biological signaling that’s occurring in these locations.
While the study of itch is a relatively small field in sensory neuroscience, these scientists are constantly learning more about this everyday sensation: how it’s triggered, how it’s transmitted through our nervous system, how it’s different from pain and other sensory circuitry, and how it’s regulated. While this blog post only scratches the surface of these processes and more details are still being discovered by scientists, the work done by the researchers in the itch field shows that even the most common phenomena can have fascinating biological underpinnings.
This post was inspired and informed by: Lay, M and Dong, X. Neural Mechanisms of Itch. Annu. Rev. Neurosci. 2020. 43:187-205.
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