Acta Dermato-Venereologica 99-7CompleteContent | Page 12

668 INVESTIGATIVE REPORT Sensory Qualities Point to Different Structural and Functional Skin Patterns in Chronic Pruritus Patients. A Translational Explorative Study Johanna HIDDING 1# , Konstantin AGELOPOULOS 1# , Manuel P. PEREIRA 1 , Heike CONRAD 2 , Hanns HATT 2 , Tobias LOTTS 1 , Nani OSADA 1 , Esther POGATZKI-ZAHN 3 , Martin SCHMELZ 4 and Sonja STÄNDER 1 Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Münster, 2 Department of Cell Physiology, Ruhr- University Bochum, 3 Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, and 4 Department of Anesthesiology and Intensive Care Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany # These authors contributed equally and should be considered as first authors. 1 Chronic pruritus (CP) is often accompanied by pares­ thetic sensations like warmth, burning and stinging. The aim of this study was to analyze, whether diver- gent sensations are linked to structural and functio- nal skin alterations in clinically diagnosed CP patients. Clinical responses to capsaicin, histamine, and to ther- mal and mechanical stimulation, intraepidermal nerve fiber density, and epidermal expression of transient receptor potential (TRP)-channels were investigated in healthy controls, and in CP patients, reporting either warmth (CP-W) or neuropathic sensations (CP-N). In CP-W, pinprick hyperalgesia and increased sensitivity to capsaicin were aligned with increased epidermal TRPV1 expression, while smaller histamine axon reflex erythema matched with significantly reduced intraepi- dermal nerve fiber density. CP-N showed earlier onset of sensations after capsaicin stimulation, significant- ly increased warmth detection threshold, and higher epidermal expression of TRPV4 compared to healthy controls. The present study contributes to the neuro- biological understanding of the divergence of sensory sensations in CP, indicating new treatment targets. Key words: sensory symptoms; TRP channels; itch; pruritus neurophysiology; nerve fiber density; quantitative sensory tes- ting. Accepted Apr 2, 2019; E-published Apr 2, 2019 Acta Derm Venereol 2019; 99: 668–674. Corr: Sonja Ständer, MD, Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Von-Esmarch-Str. 58, DE- 48149 Münster, Germany. E-mail: [email protected] C hronic pruritus (CP), one of the most frequent and scientifically underrepresented symptoms in der- matology (1, 2), usually reduces quality of life. This is increasing the need to improve the understanding and therapy of this symptom. Due to the heterogeneity of the underlying diseases, the clinical presentation of CP patients is variable (3) and the symptom itself is rarely described as pure itching. More commonly, patients describe a combination of different paresthetic sensations and sub-qualities inclu- ding burning, stinging, tingling, cold and warmth (3, 4). Most often, they report burning and stinging; qualities doi: 10.2340/00015555-3188 Acta Derm Venereol 2019; 99: 668–674 SIGNIFICANCE Chronic itch may be accompanied by other sensory symp- toms. Some patients report warmth sensation, while others describe stinging or burning in addition to the itch. Patients reporting warmth in addition to itch showed an increased painful response to mechanical stimuli, an en- hanced itch sensation after stimulation with histamine and an increased expression of TRPV1 in the skin compared to healthy controls. Patients with stinging or burning sensa- tions showed an early response to capsaicin, a lower sensi- tivity to warmth and a higher expression of TRPV4 compa- red to controls. These factors may contribute to the diverse sensations that patients with chronic itch experience. best known in the context of neuropathic pain (5) due to the functional neuronal impairment. In addition, a considerable number of patients describe cold or warmth along with the itch sensation. This is of special interest as thermosensitive ion channels of the transient receptor potential (TRP) family such as TRPA1, TRPV1, TRPV3 and TRPV4 are involved in the cutaneous itch transmis- sion (6, 7). For example, TRPV1 can be activated by the application of capsaicin, release of anandamide from sensory neurons, release of leukotriene B4 from kerati- nocytes or by acidic tissue pH, resulting in itch, warmth and burning sensation (8–11). Interestingly, TRPV1 and TRPA1 participate directly (agonist-activated) and indirectly (after stimulation of other receptors on the same cell membrane such as his- tamine or interleukin (IL) 31 receptors) in the generation of nociceptive sensations including itch signals at the cutaneous sensory nerve fibers (12). Both, and likewise other TRPs, are widely expressed on keratinocytes and cutaneous immune cells also. On keratinocytes, they contribute to thermoregulation and barrier recovery (e.g., TRPV4), or to barrier destruction (TRPV1) (13). Recent studies argue in favor of involvement of the “neuron-to-keratinocyte communication” in the genera- tion of chronic pruritus (7). Some pruritogens and growth factors released by keratinocytes may directly activate neurons and promote nerve sprouting and sensitization (7). Others recruit immune cells such as T cells and mast This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica.