Chronic Pruritus: A Review of Neurophysiology and Associated Immune Neuromodulatory Treatments

Jay M. Patel, BSc; Harry Dao Jr., MD, FAAD

Disclosures

Skin Therapy Letter. 2018;23(5):5-9. 

In This Article

Neuronal Physiology of Itch

The sensation of itch is initially transmitted through unmyelinated C-nerve fibers in the dermis and epidermis.[5] These nerve fibers can be activated by numerous molecules including those involved in acute itch sensation, such as substance P, proteinases, and histamine. Although antihistamines are effective in reducing itch from mast cell degranulation, they have little to no effect in CP.[6] Additionally, not all C-nerve fibers that transmit itch are histamine responsive.[7] Specifically, the only group of neurons that have thus far been identified as required for itch transmission are those expressing gastrin-releasing peptide receptor (GRPR).[8]

Recent work identified the central nervous system circuits that GRPR neurons utilize to transmit itch sensation to the brain in a mouse model.[9] By utilizing retrograde neuronal labeling in combination with immediate early gene expression (c-fos) after inducing itch, Mu et al. identified the spinoparabrachial pathway to be activated by pruritus.[9] Additionally, they identified direct monosynaptic connections between GRPR sensory neurons and projection neurons from the spinal cord to the parabrachial nucleus (PBN).[9] Further, inhibition of these projections resulted in diminished scratching when mice were treated with histamine.[9] Remaining work by Mu et al. focused on the PBN, a region of the brain stem implicated in arousal, thermoregulation, taste, and now itch.[10–12]

The researchers identified that neurons in the PBN are activated by itch, and that modulation of these neurons could alter itch-induced scratching when administering pruritogens like histamine or chloroquine to mice.[9] They also discovered that glutamatergic signaling in the PBN was required for itchinduced scratching.[9] Genetic deletion of the vesicular glutamate transporter resulting in an inability to release glutamate by PBN neurons resulted in the loss of itch-induced scratching for six different pruritogens including the 1-fluoro-2,4-dinitrobenzene (DNFB) induced chronic itch model.[9] Overall, this work identified the PBN as a key relay station for the central nervous system processing of itch and, moreover, elucidated a necessary role for local glutamatergic signaling for itch-induced scratching for both acute and chronic pruritus models. Understanding the neuronal circuit of itch aids in clarifying the physiology of non-dermatologic causes of itch and begins to uncover novel target cell-types for treatments. Future experiments should focus on the genetic expression pattern of these neurons to identify drug targets to modulate the neuronal activity of these itch-sensing neurons. Although brain region specific alteration of neurotransmission is not currently a viable option for the treatment of pruritus, novel therapies targeting the neuroimmune interaction have begun to be utilized in the treatment of CP.[13–17]

One of the most common causes of CP is atopic dermatitis (AD) and the role of the immune system, particularly driven by type 2 T helper (Th2) cellular responses and cytokines. Specifically, interleukin (IL)-31 has been identified as a potent pruritogen, and IL-4 and IL-13 drive skin inflammation leading to AD like features and itch.[18,19] Work in the past year from Oetjen and colleagues has furthered our understanding of how these interleukins act specifically on neurons and co-opt downstream signaling mechanisms to mediate itch.[3]

Oetjen et al. identified expression of interleukin receptors (IL-4Ra, IL13Ra1, and IL31Ra) on both human and mouse dorsal root ganglion (DRG) neurons.[3] It is important to note that both IL-4 and IL-13 bind to the IL-4Ra receptor. Utilizing intracellular calcium indicator dyes, their work demonstrated that both human and mice DRG neurons were directly activated by IL-4 and IL-13.[3] Overall, DRG responsive neurons represented a small subset of histamine positive neurons and were mainly small diameter <18 um neurons.[3] Interestingly, while DRG neurons were responsive to these interleukins, IL-4 and IL-13 were not acute pruritogens and did not potently induce itch-like behavior in rodents compared to IL-31.[3] However, when paired with administration of acute pruritogens like histamine, IL-4 caused increased itching bouts compared with histamine alone.[3] This evidence suggests that IL-4 and IL-13 could act to sensitize neurons and lower the threshold for itch.[3]

To test the necessity of IL-4 and IL-13 in the development of CP, the researchers genetically deleted the IL-4Ra receptor from DRG neurons. They subsequently discovered that in a calcipotriol mouse model of AD, both scratching behavior and histological changes due to dermatitis were ameliorated.[3] They also identified Janus kinase (JAK) signaling as the downstream mediator of IL-4Ra signaling in DRG neurons similar to immune cells expressing the receptor. Loss of neuronal JAK signaling produced similar results as the loss of IL-4Ra receptor in mice.[3] Most remarkably, however, was the discovery that in parallel to the genetic loss of JAK signaling, exogenous delivery of ruxolitinib, a JAK inhibitor, produced similar results, and was beneficial in reducing scratching in a non-inflammatory itch rodent model.[3] Overall, their findings identified a novel neuro-immune system cross-talk, whereby interleukin activation of sensory neurons mediated itch through the JAK intracellular signaling cascade.

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