Sympathetic fiber sprouting in inflamed joints and adjacent skin contributes to pain-related behavior in arthritis

J Neurosci. 2013 Jun 12;33(24):10066-74. doi: 10.1523/JNEUROSCI.5784-12.2013.


Although chronic pain is the most common symptom of arthritis, relatively little is known about the mechanisms driving it. Recently, a sprouting of autonomic sympathetic fibers into the upper dermis of the skin, an area that is normally devoid of them, was found in the skin following chronic inflammation of the rat hindpaw. While this sprouting only occurred when signs of joint and bone damage were present, it remained to be clarified whether it was a consequence of the chronic inflammation of the skin or of the arthritis and whether it also occurred in the joint. In the present study, we used a model of arthritis in which complete Freund's adjuvant (CFA) was injected into the rat ankle joint. At 4 weeks following CFA treatment, there was an increase in sympathetic and peptidergic fiber density in the ankle joint synovium. We also observed a sympathetic, but not peptidergic, fiber sprouting in the skin over the joint, which may be a consequence of the increased levels of mature nerve growth factor levels in skin, as revealed by Western blot analysis. The pharmacological suppression of sympathetic fiber function with systemic guanethidine significantly decreased the pain-related behavior associated with arthritis. Guanethidine completely suppressed the heat hyperalgesia and attenuated mechanical and cold hypersensitivity. These results suggest that transmitters released from the sprouted sympathetic fibers in the synovial membrane and upper dermis contribute to the pain-related behavior associated with arthritis. Blocking the sympathetic fiber sprouting may provide a novel therapeutic approach to alleviate pain in arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Fibers / metabolism
  • Adrenergic Fibers / pathology*
  • Analysis of Variance
  • Animals
  • Ankle Joint / innervation
  • Ankle Joint / physiopathology*
  • Arthritis / chemically induced
  • Arthritis / complications*
  • Calcitonin Gene-Related Peptide / metabolism
  • Dermis / innervation*
  • Disease Models, Animal
  • Freund's Adjuvant / toxicity
  • Gene Expression Regulation / drug effects
  • Guanethidine / administration & dosage
  • Hyperalgesia / etiology
  • Hyperalgesia / physiopathology
  • Male
  • Nerve Growth Factor / metabolism
  • Nerve Growth Factors / metabolism
  • Pain / etiology*
  • Pain / pathology*
  • Pain Measurement
  • Pain Threshold / physiology
  • Protein Precursors / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sympatholytics / administration & dosage
  • Time Factors
  • Vesicular Monoamine Transport Proteins / metabolism


  • Nerve Growth Factors
  • Protein Precursors
  • Slc18a2 protein, rat
  • Sympatholytics
  • Vesicular Monoamine Transport Proteins
  • pro-nerve growth factor, rat
  • Freund's Adjuvant
  • Nerve Growth Factor
  • Calcitonin Gene-Related Peptide
  • Guanethidine