Pathophysiology of Sensitive Skin

Itching can result from activity of specialized primary afferent neurons (“pruriceptors”) that have been shown to express certain molecular markers such as B-type natriuretic peptide and several members of the Mrgpr-family in rodents. On the other hand, neurons involved in pain processing (“nociceptors”) can also provoke itching when the activation site is restricted to an isolated tiny spot within the epidermis. Individuals classified as having sensitive skin report increased itching and pain sensations upon weak external stimuli that are not painful or itchy in the control group. Numerous possible factors could contribute to sensitive skin along the pathway of transduction of the external stimuli into peripheral neuronal signals, followed by neuronal processing, finally resulting in the perception: (a) reduced local protective factors leading to impaired skin barrier function, (b) increased production of excitatory skin mediators, (c) sensitized peripheral neurons, (d) facilitated spinal and central processing, and (e) reduced descending inhibition from the central nervous system. For all of those pathophysiological mechanisms there are clinical examples such as atopic dermatitis (a,b,c), neuropathic itching (c,e), and restless leg syndrome (d,e). However, none of these factors have been directly linked to the occurrence of sensitive skin. Moreover, individuals reporting sensitive skin are heterogeneous and a subpopulation with defined pathophysiology has not yet been identified. Given that the condition is reported in about 50% of women, and thereby includes many healthy individuals, it appears problematic to assign a definitive pathophysiological mechanism to it.

Sensitive skin is a clinical syndrome defined by the occurrence of unpleasant sensations such as burning, stinging, tingling, pricking, or itching in response to various normally innocuous physical, chemical, and thermal stimuli. These particular symptoms have led the consideration of a potential dysfunction of the intra-epidermal nerve fibers (IENF) that are responsible for pain, temperature, and itch perception. This neuronal hypothesis has just been reinforced by recent studies suggesting that sensitive skin could become assimilated to small fiber neuropathy. Meanwhile, the involvement of keratinocytes, the pre-dominant epidermal cell type, has so far mainly been considered because of their role in the epidermal barrier. However, keratinocytes also express diverse sensory receptors present on sensory neurons, such as receptors of the transient receptor potential (TRP) family, including Transient Receptor Potential Vallinoid 1 (TRPV1), one of the main transducers of painful heat which is also involved in itch transduction, and Transient Receptor Potential Vallinoid 4 (TRPV4) which is depicted as a heat sensor. While TRPV1 and TRPV4 are expressed both by sensory neurons and keratinocytes, it has recently been demonstrated that the specific and selective activation of TRPV1 on keratinocytes is sufficient to induce pain. Similarly, the targeted activation of keratinocyte-expressed TRPV4 elicits itch and the resulting scratching behavior. So, contrary to classical conception, the IENF are not the exclusive transducers of pain and itch. In light of these recent advances, this review proposes to consider the putative role of epidermal keratinocytes in the generation of the unpleasant sensations characteristic of sensitive skin syndrome.