Why Do Wounds Itch?

In the skin, a number of cell types can contribute to itch as a result of multidirectional communication. Beyond sensory nerves, these may include any epidermal or dermal cell with the capacity to participate in wound healing or inflammatory processes: keratinocytes, T and B cells, mast cells, basophils, eosinophils, and fibroblasts. These cells produce a variety of cytokines and additional mediators, many of which have been linked to itch, including interleukin (IL) 4, IL-6, IL-17, IL-22, IL-31, IL-33, cysteine and serine proteases, nerve growth factor, the neuropeptide substance P, calcitonin gene-related peptide, and endothelin, as well as serotonin, leukotrienes, and prostaglandins.

The cell body of the afferent sensory fiber in the skin is in the dorsal root ganglion, adjacent to the spinal cord. The dendrite that leaves the ganglion synapses with second order neurons in the spinal cord. The peptides most implicated in itch at this anatomic site include gastrin- releasing peptide and brain natriuretic peptide.^3,4 Following communication with a complex of spinal interneurons, a signal is sent to the brain where the sensation of itch is recognized. Instructions are then sent to motor neurons that are responsible for scratching. This behavior may relive itch or, as a result of skin perturbations induced by scratching, contribute to the itch-scratch cycle. The sensation of itch is eventually modulated, perhaps passively, as wound healing reaches as yet undefined stages in association with remodeling or actively with the production of endogenous modulators of itch, including dynorphin, an endogenous opioid peptide.

Each of the molecules listed above interact with respective cognate receptors. In addition to these receptors, a number of ion channels, including members of the transient receptor potential (TRP) family, present on sensory nerve fibers and keratinocytes contribute to the multidirectional communication that occurs in the skin. While capsaicin, the chemical that provides the sensation of heat from hot peppers, interacts with the TRP subfamily V member 1 channel, the nature of endogenous ligands of such channels, other than cationic ions, is not clear. It is not known if any pruritogens interact directly with TRP channels.

Local environmental factors also contribute to itch. These may include products of the microbiome; for example, staphylococcal delta toxin, implicated in atopic dermatitis, degranulates mast cells and may contribute directly to itch.⁵ Dryness, be it a lack of humidity or as a result of a scab or crust, also contributes to itch. A mechanism to account for itchy scabs has been provided involving the innate immune system and the associated toll-like receptor (TLR) family.⁶ It is posited that sweat ducts can become occluded in healing wounds; this occlusion is associated with biofilms produced by Staphylococcus aureus and S epidermidis. These gram-positive organisms interact with TLR2, leading to activation of kallikrein proteases, which in turn can activate the protease-activated receptor 2 that is implicated in itch.

The omission of histamine from the above discussion was purposeful. It was not because histamine is absent, but rather because it is now recognized that the contribution of histamine to clinical itches, other than some cases of urticaria, is, at best, modest.⁶ The use of antihistamines in itch, including wound itch, is a result of a lack of good therapies and not because of evidence that antihistamines help much beyond a sedative effect.

How and Why Itch Might Develop in a Wound

Wounds may occur in the setting of any of a large number of precipitants. These wounds include those associated with genetic conditions such as epidermolysis bullosa, metabolic conditions such as diabetes, ulcers from Leishmania that result from a parasitic disease transmitted by sand flies, a vector arthropod, accidents, burns, or the trauma of surgery. Wound healing proceeds through the phases of hemostasis, inflammation, proliferation, and remodeling. An open wound may itch but so can an area that has healed, particularly the itch associated with burns.

A large number of mediators have been implicated in itch and a large number of mediators are present in and around wounds. It is reasonable to conclude that there will be overlap with respect to some of these mediators. It is not known which of the wound-associated mediators can induce or inhibit pruritus. The culprits also must be present in sufficient quantity at a location in the wound where a sufficient quantity of its cognate receptor also must be located. Moisture level, pH, and signaling associated with tissue tension may all contribute to itch.

People with epidermolysis bullosa simplex frequently have itchy wounds. In contrast, people who have venous ulcers do not typically have itch in their lesions and the ulcers in people with leishmaniasis do not itch. These conditions provide templates for the study of pruritoceptive itch. Likewise, the neuropathic itch that develops and persists after the healing of some surgical incisions or burns can provide a template for the study of itch versus non-itchy lesions in these conditions. The application of the increasingly powerful approaches of proteomic and metabolic profiling to itchy and non-itchy wounds, healing and healed scars, and burns may allow for the determination of the relevant mediators. These data can then be used to develop therapies that are targeted to itch. In the interim, the treatment of wound itch is supportive rather than targeted. The simplest approaches are to maintain a balance of a clean wound along with a moist environment.