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Examining the Cross Section of Itch and Pain in AD


Aside from itch, patients with atopic dermatitis (AD) often report feeling pain as part of their disease symptoms. But do these two symptoms share any common ground?

Lars Arendt-Nielsen, Dr. Med., PhD, is the founder and director of the Center for Sensory-Motor Interaction, PI at Center for Neuroplasticy and Pain, and professor at the School of Medicine at Aalborg University in Denmark. He is also the immediate past president of International Association for the Study of Pain (IASP).

In an interview with The Dermatologist, Dr Arendt-Nielsen detailed the similarities and differences in the pathophysiology of itch and pain, highlighting the need for more research to better understand the relationship.

What is the relationship between itch and pain?
Pain and itch are two distinct yet related sensory modalities. Itch is “an unpleasant cutaneous sensation” that provokes the desire to scratch, while pain is “an unpleasant sensory experience” generating a withdrawal response to avoid tissue damage. The neuroscience of pain and itch transduction, transmission, and processing share similarities as well as dissimilarities.

Itch and pain are sensations that arise from signaling in the peripheral and central somatosensory system and, ultimately, the brain. Pain and itch are detected by similar populations of sensory neurons. Pruriceptors can be activated by nociceptive stimuli, the spinal cord, and projection neurons responding to pruritogens and algogens, and morphine may inhibit pain but facilitate itch. How the two sensations are distinguished remains a puzzle. Both systems can undergo functionally similar neuroplastic changes (hyperexcitability) and are considered key mechanisms in chronic pain and itch. The neuroscience understanding of pain is far more advanced than itch, but the two fields can learn from each other.

Following purinergic stimulation, the surrounding skin develops alloknesis (itch evoked by a normally not itchy stimulus modality, eg, touch), which parallels allodynia (pain evoked by a normally not painful stimulus modality, eg, touch). The heightened responses to itch (hyperknesis) parallel hyperalgesia (heightened responses to a pain stimulus). The hyperexcitable and neuroplastic manifestations are represented in chronic itch and pain. In human pain research, primary and secondary hyperalgesia (static and dynamic allodynia) are used. Cutaneous pain and itch-associated dysesthesias are remarkably similar.

Itch and pain are both unpleasant sensations with distinctly different perceptions, but how does the brain generate these specific sensations from fundamentally the same nerve fiber populations? Comparing brain processing between itch and pain may help to answer this question, but human brain neuroscience on itch is still in its infancy.

What pathways and characteristics of pain appear to be associated with AD?
AD is one of the itchiest skin dermatoses and affects millions of patients worldwide. Despite an extensive research effort, the mechanism of itch in AD is still unknown and it is likely that multiple parallel mechanisms are at play. Protease-activated receptors (PARs) are involved in the generation of itch in AD which differ from the histaminergic evoked itch involved in other itch conditions.

PARs are a unique family that includes four receptors belonging to the GPCR family. PARs are expressed generally in neurons, keratinocytes, and a variety of different immune cells. Their activity is regulated by the action of activating and deactivating proteases. Endogenous proteases (eg, kallikrein, cathepsin S, substance P) originate from keratinocyte and immune cells, while exogenous proteases (eg, bromelain, ficin, papain) originate from sources such as mites, fungi, cockroaches, bacteria, and plants. All the PARs, except PAR3, are known to play a role in itch transmission. For instance, PAR1 is correlated with histamine-dependent itch. Contrary, PAR2 and PAR4 are associated with histamine-independent itch, as H1 histamine receptor antagonists failed to inhibit scratching induced by PAR2 and PAR4 activation. They stimulate different subpopulations of afferent sensory neurons. Patients with certain chronic itch conditions present with elevated levels of proteases in their skin, which can potentially activate their corresponding receptors, such as PAR2. 

The activation of PARs occurs through proteolytic cleavage of their extracellular N-terminus. This process in fact leads to cleavage of an amino terminus sequence that acts as a tethered ligand upon activation of PARs. For PAR2, a sequence composed of Ser-Leu-Ile-Gly-Arg-Leu (SLIGRL) is exposed. The concentration of SLIGRL has been measured to be high in patients with chronic itch such as in AD, hence AD does not respond to antihistamines. Patients with AD show signs of intralesional and extralesional nonhistaminergic itch sensitization as a result of alterations of the central processing of itch.

What additional research is needed to improve the understanding of itch and pain in skin diseases, such as atopic dermatitis?
Chronic itch, similarly to chronic pain, is a common clinical problem that is associated with a markedly reduced quality of life for affected patients. Itch is a major symptom in several of the most prevalent dermatologic diseases (eg, AD, psoriasis, or urticaria), but it also occurs in a variety of noncutaneous conditions (eg, related to peripheral neuropathy, renal insufficiency, or cholestasis). Chronic itch is often difficult to treat, has a detrimental impact on sleep quality as well as concentration, and is consistently linked to increased rates of anxiety and depression.

There is generally an unmet need for treating chronic itch in general and particularly in AD. For nonhistaminergic and neurogenic itch conditions, there are few treatment options, and patients suffer immensely from chronic itch. So, a concerted action between industry and academia is urgently needed to develop new and better antipruritic drugs. Recently, the monoclonal antibody dupilumab was approved after showing very high anti-inflammatory and antipruritic efficacy in patients with moderate to severe AD. Dupilumab binds to the alpha subunit of the IL-4Rα receptor, making it a receptor antagonist. The monoclonal antibody nemolizumab, which antagonizes IL-31RA by blocking IL-31 signaling on its effector cells, including peripheral neurons, is likewise in clinical development.

Any other thoughts or comments you would like to add?
As there is a lot of cross-fertilization between pain and itch, we have just published the first book reviewing the similarities and dissimilarities between the two interlinked sensory modalities.1 The IASP has just launched a special interest group on pain and itch, which likewise will promote cross-fertilization between the two fields to improve pain management and itch management.2

1. Yosipovitch G, Arendt-Nielsen L, Andersen H, eds. Itch and Pain: Similarities, Interactions, and Differences. Wolters Kluwer; 2020.

2. Itch. International Association for the Study of Pain. Accessed January 24, 2021.


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