Exp Dermatol 1999: 8: 274–281 Copyright C Munksgaard 1999 Printed in Denmark ¡ All rights reserved ISSN 0906-6705 Hair growth-modulation by adrenergic drugs Peters EMJ, Maurer M, Botchkarev VA, Gordon DS, Paus R. Hair E. M. J. Peters 1 , M. Maurer 1,2 , growth-modulation by adrenergic drugs. V. A. Botchkarev 1 , Exp Dermatol 1999: 8: 274–281. C Munksgaard, 1999 D. S. Gordon 3 and R. Paus 1 1 Department of Dermatology, Charite ´, Humboldt- Abstract: Since we have recently shown that the b 2 -adrenoreceptor (b 2 - Universita ¨t zu Berlin, D-10117 Berlin, Germany; AR) expression of selected regions of the hair follicle (HF) epithelium as 2 Current address: Div. of Exp. Pathology, Beth well as the number of adrenergic nerve fibers in murine skin change in a Israel Deaconess Medical Center Harvard hair cycle-dependent manner, this has raised the possibility that adre- Medical School, Boston, MA 02215, USA; nergic nerves may exert ‘‘trophic’’ functions during HF cycling. To further 3 Department of Histology, Medical Institute, Chuvash State University, Russia explore this concept, we have investigated the effect of neuro-pharmaco- logical manipulations on hair growth (anagen) induction in quiescent tel- ogen mouse skin in vivo. Here, we demonstrate that subcutaneous injections of the noradrenaline (NA)-depleting agent guanethidine, or of the neur- otoxin 6-hydroxydopamine, but not of the b 2 -AR agonist isoproterenol induce a premature onset of anagen in the lower back skin of C57BL/6 mice. On day 20 after the start of treatment, more than 80% of the guanethidine-treated mice and ca. 65% of the 6-hydroxydopamine-treated (6-OHDA) mice exhibited premature skin darkening and hair growth at the site of drug application, whereas less than one-third of all control animals Key words: hair cycle – neurotransmitter – showed macroscopic signs of anagen development. This was confirmed noradrenaline – tyrosine hydroxylase – 6- by histology, demonstrating mature anagen VI HFs only at the immediate hydroxydopamine – guanethidine – isoproterenol site of treatment with guanethidine or 6-OHDA as opposed to resting R. Paus, MD, Dept of Dermatology, telogen HFs in the neighboring untreated skin area. This observation University Hospital Eppendorf further supports the concept that sympathetic nerves are intimately in- University of Hamburg volved in hair growth control and invites one to explore the neuro-phar- D-20246 Hamburg, Germany macological manipulation of piloneural interactions as a novel thera- e-mail: paus/uke.uni-hamburg.de peutic strategy for the management of hair growth disorders. Accepted for publication 29 October 1998 Introduction Due to its rich innervation, its composition of ecto- derm-, neural crest- and mesenchyme-derived cells, and its continuous remodeling, the HF offers an ideal model system for the study of neuroectoderm- al–mesenchymal interactions (1–3). Between resting (telogen), growth (anagen) and regression (catagen), piloneural interactions may assist in orchestrating the complex pattern of epithelial proliferation, dif- ferentiation, and apoptosis that drive the hair cycle (4). The potential usefulness of neuro-pharmaco- logical manipulations of piloneural interactions for the management of hair growth ‘‘disorders’’ (c.f. (1, Abbreviations: b 2 -AR: b 2 -adrenoreceptor; HF: hair follicle; IR: immunoreac- tive; NA: noradrenaline; 6-OHDA: 6-hydroxydopamine; ORS: outer root sheath; TH: tyrosinehydroxylase; TBS: Tris buffered saline; SG: sebaceous gland. 274 3)), can be conveniently investigated in this readily accessible model system (2, 3, 5). Sympathetic nerve fiber endings in hairy mam- malian skin form multiple neuro-muscular junc- tions with the arrector pili muscle, which inserts into the HF outer root sheath (ORS) at the level of the bulge region (5, 6), the probable seat of epithelial HF stem cells (7). Adrenergic nerve fibers also ap- pear as single nerve fibers in the dermis (5, 8) as well as around blood vessels in the subcutis (5, 9). Stimu- lation of b-ARs affects epidermal proliferation and differentiation (10–12) and several lines of circum- stantial evidence support that sympathetic skin nerves are involved in HF growth (13–17). For ex- ample, loss of adrenergic skin innervation has been reported to be associated with the interruption of hair follicle morphogenesis until recovery of inner- vation (15, 16) while experimentally induced adre- nergic skin hyperinnervation following denervation was associated with premature HF development and hair growth (14, 17).