Abstract
Joint pain is a distressing symptom of arthritis, and it is frequently persistent even after treatments which reduce local inflammation. Continuous production of algogenic factors activate/sensitize nociceptors in the joint structures and contribute to persistent pain, a challenging and difficult condition to treat. TNF is a crucial cytokine for the pathogenesis of several rheumatic diseases, and its inhibition is a mainstay of treatment to control joint symptoms, including pain. Here, we sought to investigate the inflammatory changes and the role of TNF in dorsal root ganglia (DRG) during persistent hypernociception after the resolution of acute joint inflammation. Using a model of antigen-induced arthritis, the peak of joint inflammation occurred 12–24 h after local antigen injection and was characterized by an intense influx of neutrophils, pro-inflammatory cytokine production, and joint damage. We found that inflammatory parameters in the joint returned to basal levels between 6 and 8 days after antigen-challenge, characterizing the resolving phase of joint inflammation. Mechanical hyperalgesia was persistent up to 14 days after joint insult. The persistent nociception was associated with the inflammatory status of DRG after cessation of acute joint inflammation. The late state of neuroinflammation in the ipsilateral side was evidenced by gene expression of TNF, TNFR2, IL-6, IL-1β, CXCL2, COX2, and iNOS in lumbar DRG (L3-L5) and leukocyte adhesion in the lumbar intumescent vessels between days 6 and 8. Moreover, there were signs of resident macrophage activation in DRG, as evidenced by an increase in Iba1-positive cells. Intrathecal or systemic injection of etanercept, an agent clinically utilized for TNF neutralization, at day 7 post arthritis induction, alleviated the persistent joint hyperalgesia by specific action in DRG. Our data suggest that neuroinflammation in DRG after the resolution of acute joint inflammation drives continuous neural sensitization resulting in persistent joint nociception in a TNF-dependent mechanism.
Highlights
The inflammatory process, a protective response against various infectious and sterile noxious stimuli, is responsible for the elimination of the stressor agent resulting in a return to tissue homeostasis [1, 2]
Joint pain is a common and debilitating symptom in arthritic patients and different molecules produced in inflammatory environment directly activate peripheral sensory innervation, reducing the threshold for the nociceptor signal transduction
Using an acute model of arthritis in mice, we demonstrated here that joint nociception is detected for several days after complete resolution of acute joint inflammation and that acute neutrophilic inflammation in an antigen-induced arthritis (AIA) model was spontaneously resolved
Summary
The inflammatory process, a protective response against various infectious and sterile noxious stimuli, is responsible for the elimination of the stressor agent resulting in a return to tissue homeostasis [1, 2]. Continuous inflammation is associated with persistent harmful stimuli or failed inflammatory resolution [3,4,5]. The resolution of inflammation is a wellcontrolled process resulting in a reduction of leukocyte accumulation and an increase in neutrophil apoptosis, macrophages reprogramming, and functional recovery of tissue. Pain is an important cardinal signal associated with loss of function. Previous studies have demonstrated that articular hyperalgesia may persist after resolution of inflammation in a model of antigen inducedarthritis [6, 7]. The mechanism which coordinates this persistent articular pain following inflammatory cessation is unknown
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