Acta Dermato-Venereologica 99-6CompleteContent | Page 17

587 INVESTIGATIVE REPORT Neuromedin B Induces Acute Itch in Mice via the Activation of Peripheral Sensory Neurons Sarah EHLING 1,2 , Tomoki FUKUYAMA 1 , Mei-Chuan KO 3 , Thierry OLIVRY 4,5 , Wolfgang BÄUMER 1,2 Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, North Carolina, USA, Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany, 3 Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, 4 Department of Clinical Sciences, College of Veterinary Medicine, and 5 Comparative Medicine Institute, North Carolina State University, North Carolina, USA 1 2 Neuromedin B is expressed in nociceptive and itch- sensitive dorsal root ganglia neurons, but its periphe- ral pruritogenic potential is not well described. The potential of neuromedin B as a pruritogen and pro-in- flammatory peptide in the skin was tested in vivo in an acute model in mice and monkeys as well as an allergic dermatitis model in mice. To identify the underlying mechanisms in vitro real time PCR analysis for neu- romedin B and its receptor expression in murine mast cells and dorsal root ganglia as well as functional calci- um imaging in the ganglia was applied. Neuromedin B induces itch when injected intradermally, and the pe- ripheral signal is likely transmitted through the activa- tion of dorsal root ganglia. Thus, neuromedin B could be an interesting new therapeutic target for peripheral processing of itch at the level of sensory neurons. Key words: acute itch; dorsal root ganglia, mast cells; neuro- medin B; allergic dermatitis. Accepted Feb 7, 2019; E-published Feb 8, 2019 Acta Derm Venereol 2019; 99: 587–593. Corr: Sarah Ehling, Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Freie Universität Berlin, Koserstrasse 20, DE-14195 Berlin, Germany. E-mail: [email protected] A cute pruritus (itch) is a protective alarm signal that induces a scratch response to remove hazards from the skin, such as toxins or parasites. Dermatoses were the 18 th leading cause of health burden worldwide assessed by the Global Burden of Skin Disease in 2010 (1). Itch is a symptom of a variety of inflammatory skin conditions such as atopic dermatitis (AD) or psoriasis. Particularly chronic itch is a treatment challenge in dermatology (2). Therefore, there is an urgent need for finding strategies to control itch more efficiently that requires a better under- standing of the underlying itch and scratch mechanisms. Pruritus can have its origin directly in the periphery (skin), or it can develop in the central nervous system (CNS) via haematogenic or neurogenic mediators (2, 3). Pruritogenic mediators such as cytokines, proteases, leukotrienes and histamine activate itch-sensing nerve endings in the skin (4, 5). In the last decade, animal mo- dels helped to further understand the transmission of the itch signal from the periphery to the CNS and identified pruritogens and their receptors. It is known, that mast cells are located in close proximity to sensory nerve SIGNIFICANCE Neuromedin B is expressed in neurons involved in itch but its peripheral pruritogenic potential is not well described. Neuromedin B induces itch in mice and monkeys when in- jected into the skin. Most likely this itch signal is transmit- ted through the activation of peripheral neurons. So far the pathogenesis of pruritus is quite complex. It remains important to investigate and subsequently develop novel mechanism-based strategies to treat pruritus and poss­ ibly provide a locus for pharmacological control of pruritus. Thus, Neuromedin B could be an interesting new therapeu- tic target for peripheral processing of itch at the level of sensory neurons. endings in the skin and that they communicate through an intercellular network that includes histamine, tryptase, neuropeptides, leukotrienes, prostaglandin D2, cytokines and chemokines (6). Among these neuropeptides is the mammalian bombesin-like peptide family and its mem- bers neuromedin B (NMB) and gastrin-releasing peptide (GRP). The C-terminal amidated sequence of NMB, Leu- Trp-Ala-Thr-Gly-His-Phe-Met-NH 2 , is highly conserved across mammalian species. Neuromedin B is found in the pituitary gland, pancreas, adrenal medulla, gastroin- testinal tract and the central nervous system (CNS) (7). In the CNS, NMB induces scratching when injected intrathecally in mice or intracerebroventrically in rats (8, 9). Neuromedin B is also expressed in peripheral ner- ves, the trigeminal ganglion and the dorsal root ganglia (DRG). In the latter, NMB is located in nociceptive and itch-sensitive neurons. If injected into the plantar area of the foot in mice, it induces neurogenic inflammation and thermal nociception (10). Neuromedin B signals exclusively through its receptor NMBR, a G protein- coupled receptor (11). This receptor is expressed on cells of the immune and endocrine systems, urogenital and respiratory tracts and the CNS (11). Mishra et al. (10) also showed that NMBR is expressed on peripheral nerves, the trigeminal and DRG, where it is mostly co- expressed with the transient receptor potential cation channel subfamily V member 1 (TRPV1)+ and calcitonin gene-related peptide (CGRP)+ neurons. Interestingly, recent studies using microarray-based transcriptome profiles, identified an upregulation of NMB in the atopic skin in dogs, which is of importance This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica. doi: 10.2340/00015555-3143 Acta Derm Venereol 2019; 99: 587–593