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

Abstract

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 A␦ 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 A␦ 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.

Remaining Pain in Early Rheumatoid Arthritis Patients Treated With Methotrexate

“…Proinflammatory cytokines like tumor necrosis factor (TNF) and interleukin 6 (IL‐6) are both of specific importance in RA pathogenesis, and specific cytokine blockade has been shown beneficial 22, 23. Both TNF and IL‐6 also affect pain thresholds in experimental arthritis 24, 25, as well as long‐term sensitization of joint nociceptors 26. In RA, general hyperalgesia to mechanical and thermal stimuli have been reported 27, and decreased pain thresholds over nonpainful areas were also shown in established RA, but not in early disease, suggesting the impact of long‐term inflammation in this context 28.…”

Antinociceptive effects of tumor necrosis factor α neutralization in a rat model of antigen‐induced arthritis: Evidence of a neuronal target

“…Adult male Wistar rats (n ϭ 30; ages 13-17 weeks, 300-460 gm) (supplied by the University of Jena, Jena, Germany) were used because the model of kaolin/carrageenan-induced inflammation is well established in these rats (6,38). For comparison with behavioral experiments, further recordings were performed in adult female Lewis rats (n ϭ 12; ages 12-14 weeks, 210-225 gm) (Charles River).…”

“…We identified nerve fibers with receptive fields in the knee joint by mechanical stimulation with a blunt glass rod. According to their conduction velocities, fibers were classified as C (Յ1.25 m/sec), A␦ (1.25-10 m/sec), and A␤ fibers (Ն10 m/sec) (38). For this purpose, the mechanically identified receptive field was stimulated with a bipolar electrode (pulses of 1-10V and 0.5 m/sec duration), and the distance between the electrode and the recording site was measured.…”

Increased hyperpolarized [1‐13C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized 13C‐labelled bicarbonate

“…During inflammation, sensory neurones innervating joints become sensitized,2, 3, 4, 5 which contributes to the tenderness of arthritic joints 6, 7. The inflammatory milieu contains many mediators, including protons, and early measurements of synovial fluid pH from rheumatoid arthritis (RA) patients found a pH of 7.21, compared with 7.43 in healthy subjects 8.…”