Sensitization of unmyelinated sensory fibers of the joint nerve to mechanical stimuli by interleukin-6 in the rat: an inflammatory mechanism of joint pain

Arthritis Rheum. 2007 Jan;56(1):351-9. doi: 10.1002/art.22282.


Objective: Pain during mechanical stimulation of the joint and spontaneous pain are major symptoms of arthritis. An important neuronal process of mechanical hypersensitivity of the joint is the sensitization of thin myelinated Adelta fibers and unmyelinated C fibers innervating the joint. Because interleukin-6 (IL-6) is a major inflammatory mediator, we investigated whether this cytokine has the potential to sensitize joint afferents to mechanical stimuli.

Methods: In electrophysiologic experiments conducted on anesthetized rats, action potentials were recorded from afferent fibers supplying the knee joint. Responses to innocuous and noxious rotation of the tibia against the femur in the knee joint were monitored before and 1-2 hours after injection of test compounds into the joint cavity.

Results: Injection of IL-6 and coinjection of IL-6 plus soluble IL-6 receptor (sIL-6R) caused a gradual increase in the responses of C fibers to innocuous and noxious rotation within 1 hour. The increase in responses to IL-6 and IL-6 plus sIL-6R was prevented by coadministration of soluble glycoprotein 130 (sgp130), but sgp130 did not reverse established mechanical hyperexcitability. Responses of Adelta fibers were not altered by the compounds. While injection of sIL-6R alone into the normal knee joint did not influence responses to mechanical stimulation, injection of sIL-6R into the acutely inflamed knee joint caused an increase in responses.

Conclusion: IL-6 has the potential to sensitize C fibers in the joint to mechanical stimulation. Thus, IL-6 contributes to mechanical hypersensitivity, most likely due to an action of IL-6 on nerve fibers themselves.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Cytokine Receptor gp130 / antagonists & inhibitors
  • Cytokine Receptor gp130 / pharmacology
  • Drug Combinations
  • Humans
  • Interleukin-6 / pharmacology*
  • Joints / innervation*
  • Joints / physiopathology
  • Male
  • Nerve Fibers, Unmyelinated / drug effects*
  • Nerve Fibers, Unmyelinated / physiology
  • Neurons, Afferent / drug effects*
  • Neurons, Afferent / physiology
  • Pain Threshold / drug effects*
  • Pain Threshold / physiology
  • Physical Stimulation / adverse effects
  • Rats
  • Rats, Wistar
  • Recombinant Proteins
  • Stress, Mechanical


  • Drug Combinations
  • Interleukin-6
  • Recombinant Proteins
  • Cytokine Receptor gp130