Interleukin‐17 sensitizes joint nociceptors to mechanical stimuli and contributes to arthritic pain through neuronal interleukin‐17 receptors in rodents

Abstract

Objective. Interleukin-17 (IL-17) is considered a proinflammatory cytokine, but whether neuronal IL-17 receptors contribute to the generation of arthritic pain is unknown. This study was undertaken to explore whether IL-17A acts on neurons, whether it sensitizes joint nociceptors, and whether neutralization of IL-17 is antinociceptive.Methods. We recorded action potentials from rat joint nociceptors after intraarticular injection of IL-17A. We studied the expression of the IL-17A receptor in the rat dorsal root ganglia (DRG), explored the effect of IL-17A on signaling pathways in cultured rat DRG neurons, and using patch clamp recordings, monitored changes of excitability by IL-17A. We tested whether an antibody to IL-17 influences pain behaviors in mice with antigen-induced arthritis (AIA).Results. A single injection of IL-17A into the rat knee joint elicited a slowly developing and long-lasting sensitization of nociceptive C fibers of the joint to mechanical stimuli, which was not attenuated by neutralizing tumor necrosis factor ␣ or IL-6. The IL-17A receptor was visualized in most rat DRG neurons, the cell bodies of primary sensory neurons. In isolated and cultured rat DRG neurons, IL-17A caused rapid phosphorylation of protein kinase B and ERK, and it rapidly enhanced excitability. In mice with unilateral AIA in the knee, an antibody against IL-17 improved the guarding score and reduced secondary mechanical hyperalgesia at the ipsilateral paw.Conclusion. Our findings indicate that IL-17A has the potential to act as a pain mediator by targeting IL-17 receptors in nociceptive neurons, and these receptors are particularly involved in inflammation-evoked mechanical hyperalgesia.

A de novo gain-of-function mutation in SCN11A causes loss of pain perception

“…Gait abnormalities of the ipsilateral hindlimb were scored as previously described 41 : 0, normal walking; 1, slight limping; 2, persistent severe limping (still touching the floor); 3, severe limping with partial guarding of ipsilateral hindlimb (sometimes not touching the floor); 4, mainly guarding ipsilateral hindlimb (most times not touching the floor); 5, no walking at all.…”

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.…”

A Promising New Approach for the Treatment of Inflammatory Pain: Transfer of Stem Cell-Derived Tyrosine Hydroxylase-Positive Cells

“…Gait abnormalities (guarding score) were scored: 0 = normal walking, 1 = slight limping, 2 = persistent severe limping (still touching the floor), 3 = severe limping with partial guarding of ipsilateral hindlimb (sometimes not touching the floor), 4 = mainly guarding of ipsilateral hindlimb (most times not touching the floor), and 5 = no walking at all [18]. For testing of secondary mechanical hyperalgesia at the paw, mice were placed into the testing device, and after accommodation to the environment the mechanical pain threshold was determined with a dynamic plantar aesthesiometer (Ugo Basile, Comerio, Italy) which applied increasing pressure (stimulus increase rate 1 g/s; cut-off value 10 g) to the paw [16].…”

“…Statistical significance was calculated with the SPSS software package (v.16.0, Chicago, IL, USA) and accepted for p < 0.05. The group size for studies on AIA was estimated from our previous studies [16, 18, 20]. …”