Don’t Scratch That! The Evolution of Itch

Illustration by Mimi Shang

Illustration by Mimi Shang

We all itch subconsciously to gain relief from minor disturbances on our skin. But most of us have probably experienced itches that go far beyond this level to the point where an itch can take over your entire mind for several minutes. As an example of a more extreme case, a patient with HIV from Massachusetts developed a severe deep crawling itch on the right side of her scalp in response to shingles medication. Her scratching intensified at night and one unfortunate morning she woke up to find green liquid on her hands. When she got to the hospital she was immediately admitted into an emergency department. She had scratched through her skull and into her brain.
Scientists classify itches in four categories: pruriceptive (skin irritation and inflammation), neuropathic (chronic itching due to nerve damage), neurogenic (activation of the CNS without stimulus), and psychogenic (mental illness). Pruriceptive itch, the most common type, can be triggered by stimulation of pruriceptors by mechanical, thermal and even chemical mediators such as histamines, which are part of our body’s immune response.
It is easy to think that the need to itch is simply a milder version of a pain response, but modern research tells us that this is not so. The two schools of thought on the topic are the intensity theory, which makes the claim that the same sensory neurons can result in pain or itch based on the intensity of the stimulus, and the labeled line theory, which claims that these two sensations lie on entirely separate neuronal pathways.
The Center for the Study of Itch at WUSTL is the first research center dedicated to studying chronic itch and they have done a lot of work to characterize the signaling mechanisms of itch and pain. The researchers working at this center discovered the first itch specific receptor, GRPR, which ultimately led to the hypothesis that the itch and pain signals are transmitted on separate pathways. But a recent paper from this lab looked at how Grp (gastrin-releasing peptide) positive neurons are capable of amplifying signals of pain or itch depending on the intensity of the stimulus. This paper modifies their earlier theory that itch and pain are the result of entirely different signaling pathways.
The authors point out that the Pain and Itch result in very different biological responses from a person, “Pain generates a withdrawal response to avoid tissue damage, while itch elicits scratching to remove irritants”. The authors also make the important observation that pain has the ability to suppress itch which is shown when the mechanical pain of a scratch masks an itch, but never see an itchy sensation relieve pain. This led the authors to believe that pain and itch have common neuronal paths but somehow our CNS is able to distinguish these sensations. Their new selectivity theory claims that itch stimuli are itch neuron specific while painful stimuli activates a wide range of neurons that ultimately inhibits the itch sensation while producing the pain sensation.
According to the researchers, the Grp+ neurons are strongly activated by pain stimuli but itch stimuli are able to leak into the receptors and weakly trigger a response. It is difficult to accurately describe how the intensity of the itch activation and pain activation differ, but the researchers attribute the pruritogen signal to weak synaptic connections and a smaller percentage of itch responsive primary neurons.
So if the itch response characterizes the lower end of the Grp+ neuron activation, you may have guessed that there is an upper limit to how strong of a pain signal can be transmitted by this pathway. The researchers also discovered that an overly intense signal would trigger a negative feedback loop involving the endogenous opioid system which inhibits the overactive Grp+ neurons. By having this threshold, the Grp+ neurons are able to maintain sensitivity to weaker itch inputs.
Recently many researchers have discovered new itch stimulus specific receptors, suggesting that Itch is most likely a combination of the intensity and labelled line theories. An important example is the Natriuretic peptide b neurotransmitter, or Nppb, which is necessary to transmit the itch response in mice. In fact, simply injecting this peptide into a mouse is able to elicit a scratch response. Researchers in this study recognize that Grp may be the primary neurotransmitter for itch but they also maintain that Nppb acts on receptors upstream of Grp and is able to transmit the itch response on its own.
Another lab at WUSTL, CSI, is working on characterizing Mrgpr receptors, which are expressed in sensory nerves and are itch specific receptors that operate independent of the presence of histamine. This is incredibly important because many chronic itches cannot be treated with antihistamines, thus suggesting that there are many unique itch receptors, such as Mrgpr, that won’t respond to conventional treatments due to differences in mode of action.
Fig 1: A cartoon of how the stimulation of multiple itch specific receptors result in the sensation of an itch.
Evolution suggests that we evolved the itch mechanism to rid ourselves of disease causing insects and plant matter. But there is little evidence suggesting that scratching gives any immunity benefits. I noticed that these research articles failed to provide an explanation as to why itching feels pleasurable. If Dr. Sun is correct in saying that itch shares a pathway with pain, then I find it very ironic that the former can feel so satisfying at times. I encourage the reader to consider times that they have felt itchy and try and identify a cause for the response. Try to see if an itch response has ever helped you avoid exposure to dangerous agents.

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