To the Editor:

My colleagues and I thank Dr. Straub for his letter regarding our article. As he noted, there appears to be significant heterogeneity in the literature concerning the changes in sympathetic innervation that occur in different inflammatory pain states (1–7). We agree that changes in the sensory and sympathetic innervation in an inflamed tissue depend on a variety of factors, including the type of model, the tissue being investigated, postmortem examination, and methods of tissue collection and storage.

As stated in the Discussion of our report, robust sprouting of tyrosine hydroxylase–positive postganglionic sympathetic nerve fibers was observed in the inflamed synovium of the painful arthritic joints in mice, and anti–nerve growth factor therapy blocked this sprouting. We attempted to address these differences in our results versus those of others by stating that “… several reports have suggested that sympathectomy attenuates disease progression and/or pain in arthritis (18–20) [8–10 herein], although sympathectomy-induced enhancement of disease and/or pain in arthritis has also been reported (21–23) [11–13 herein]. Whether these differences are due to the different species, models of arthritis, or methods of performing sympathectomy that were used in these studies remains unclear.”

Given the limitations in terms of both word count and number of references allowed in this type of communication, the article was not meant to be a systematic review of the heterogeneous literature concerning the changes that sympathetic nerve fibers undergo in different inflammatory pain states. Rather, the study was intended to demonstrate that significant sprouting of sensory and sympathetic nerve fibers can occur in the painful inflammatory joint. Thus, while the role of sensory and sympathetic nerve plasticity in inflammatory disease–related pain states is not completely understood, the present findings suggest that significant neuroplasticity can occur, and we agree that further studies are needed to understand the physiologic significance of the neuroplasticity of sensory and sympathetic nerve fibers (whether it be an increase or decrease) that frequently occurs in inflammatory states.

  • 1
    Widenfalk B. Sympathetic innervation of normal and rheumatoid synovial tissue. Scand J Plast Reconstr Surg Hand Surg 1991; 25: 313.
  • 2
    Straub RH. Autoimmune disease and innervation. Brain Behav Immun 2007; 21: 52834.
  • 3
    Pereira da Silva JA, Carmo-Fonseca M. Peptide containing nerves in human synovium: immunohistochemical evidence for decreased innervation in rheumatoid arthritis. J Rheumatol 1990; 17: 15929.
  • 4
    Mapp PI, Kidd BL, Gibson SJ, Terry JM, Revell PA, Ibrahim NB, et al. Substance P-, calcitonin gene-related peptide- and C-flanking peptide of neuropeptide Y-immunoreactive fibres are present in normal synovium but depleted in patients with rheumatoid arthritis. Neuroscience 1990; 37: 14353.
  • 5
    Miller LE, Justen HP, Scholmerich J, Straub RH. The loss of sympathetic nerve fibers in the synovial tissue of patients with rheumatoid arthritis is accompanied by increased norepinephrine release from synovial macrophages. FASEB J 2000; 14: 2097107.
  • 6
    Harle P, Mobius D, Carr DJ, Scholmerich J, Straub RH. An opposing time-dependent immune-modulating effect of the sympathetic nervous system conferred by altering the cytokine profile in the local lymph nodes and spleen of mice with type II collagen–induced arthritis. Arthritis Rheum 2005; 52: 130513.
  • 7
    Da Silva JA, Fonseca JE, Graca L, Moita L, Carmo-Fonseca M. Reinnervation of post-arthritic joints in the rat. Clin Exp Rheumatol 1996; 14: 4351.
  • 8
    Herfort R, Nickerson SH. Relief of arthritic pain and rehabilitation of chronic arthritic patient by extended sympathetic denervation. Arch Phys Med Rehabil 1959; 40: 13340.
  • 9
    Howell TH. Relief of pain in rheumatoid arthritis with tetraethylammonium bromide. Lancet 1950; 1: 204.
  • 10
    Levine JD, Moskowitz MA, Basbaum AI. The contribution of neurogenic inflammation in experimental arthritis. J Immunol 1985; 135 Suppl: 843s847s.
  • 11
    Sluka KA, Lawand NB, Westlund KN. Joint inflammation is reduced by dorsal rhizotomy and not by sympathectomy or spinal cord transection. Ann Rheum Dis 1994; 53: 30914.
  • 12
    Lorton D, Lubahn C, Klein N, Schaller J, Bellinger DL. Dual role for noradrenergic innervation of lymphoid tissue and arthritic joints in adjuvant-induced arthritis. Brain Behav Immun 1999; 13: 31534.
  • 13
    Lam FY, Ferrell WR. Neurogenic component of different models of acute inflammation in the rat knee joint. Ann Rheum Dis 1991; 50: 74751.

Patrick W. Mantyh PhD, JD*, * University of Arizona, Tucson, AZ.