Brain, Behavior, and Immunity 13, 315–334 (1999) Article ID brbi.1999.0564, available online at http://www.idealibrary.com on Dual Role for Noradrenergic Innervation of Lymphoid Tissue and Arthritic Joints in Adjuvant-Induced Arthritis Dianne Lorton,* Cheri Lubahn,* Nathan Klein,* Jill Schaller,* and Denise L. Bellinger² *Hoover Arthritis Center, Sun Health Research Institute, P.O. Box 1278, Sun City, Arizona 85372; and ²Department of Neurobiology and Anatomy, Box 603, University of Rochester School of Medicine, 601 Elmwood Avenue, Rochester, New York 14642 The role of noradrenergic innervation in the disease outcome of adjuvant-induced arthri- tis (AA) has been examined following (1) systemic administration of guanethidine and (2) local application of 6-hydroxydopamine (6-OHDA) into the lymph nodes that drain the hind limbs (DLN). Sympathetic denervation by these different neurotoxins produced directionally opposite effects on disease outcome. These conflicting findings could be ex- plained from differential denervation of sympathetic nerves in key target tissues that result from different routes of neurotoxin administration. Alternatively, these conflicting data could be due to differences in the mechanisms by which guanethidine and 6-OHDA destroy sympathetic nerve terminals. In this study, we compared disease outcome in AA following systemic and local DLN application of 6-OHDA to determine whether the route of adminis- tration is important to the development and progression of AA. Bilateral local DLN applica- tion of 6-OHDA or vehicle was performed 1 day before injection of Freund’s complete adjuvant (CFA) to induce arthritis. For systemic denervation, 6-OHDA or vehicle was given by ip injections on days 1, 3, and 5 prior to CFA challenge and then once a week. Local DLN application of 6-OHDA resulted in significant increases in dorsoplantar width in arthritic rats by 27 days following CFA treatment compared to those of non-denervated arthritic rats. In contrast, systemic denervation in arthritic rats significantly decreased dor- soplantar widths 27 days after CFA treatment compared to those in sympathetically intact arthritic animals. X-ray analysis confirmed these findings. Further, local DLN application of 6-OHDA exacerbated the disease regardless of whether the neurotoxin was administered prior to immunization with CFA or closer to the time of disease onset. Our findings indicate that the route of 6-OHDA administration for denervation of sympathetic innervation is an important parameter in determining disease outcome, presumably due to differential sympathetic denervation of target tissues that are involved in disease development and progression. 6-OHDA administration into local DLN denervated these lymph nodes, but spared sympathetic innervation of the hind limbs, a pattern of sympathetic denervation that resulted in disease exacerbation. In contrast, systemic 6-OHDA administration which denervated both the arthritic joints and the secondary lymphoid organs attenuated the sever- ity of AA. This study supports a dual role for NA innervation in modulating the severity of AA by innervation of the arthritic joints and lymphoid organs.  1999 Academic Press Key Words: neural–immune; autoimmune diseases; adjuvant-induced arthritis; norad- renergic innervation. INTRODUCTION The sympathetic nervous system (SNS) is an important modulator of the immune system. Research in animal models of many autoimmune disorders have demon- strated that reduced sympathetic outflow alters the onset and progression of autoim- munity (Chelmicka-Schorr, Checinski, & Arnason, 1988; Chelmicka-Schorr, Kwas- niewski, Thomas, & Arnason, 1989; Agius, Checinski, Richman, & Chelmicka-Shorr, 1987; Bellinger, Ackerman, Felten, Lorton, & Felten, 1989; Brenneman, Moynihan, Grota, Felten, & Felten, 1993). In general, these studies indicate a protective role for 315 0889-1591/99 $30.00 Copyright  1999 by Academic Press All rights of reproduction in any form reserved.