Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats

Abstract

Objective. During inflammation in the joint, normal joint movements are usually painful. A neuronal mechanism for this form of mechanical hyperalgesia is the persistent sensitization of joint nociceptors to mechanical stimuli. Because tumor necrosis factor (TNF) is a major mediator of joint inflammation, we undertook the present study both to explore the potential of TNF to sensitize joint nociceptors to mechanical stimuli and to address the cellular mechanism involved.Methods. In anesthetized rats, action potentials (APs) were recorded from sensory nociceptive A␦ fibers and C fibers supplying the knee joint. We monitored responses to rotation of the knee joint at innocuous and noxious intensities. TNF, etanercept, and a p38 inhibitor were injected into the knee joint, and the cyclooxygenase (COX) inhibitor diclofenac was administered intraperitoneally. APs were also recorded in isolated cultured dorsal root ganglion (DRG) neurons in order to test for changes in neuronal excitability induced by TNF.Results. A single application of TNF into the normal knee joint caused a significant persistent sensitization of nociceptive sensory fibers to mechanical stimuli applied to the joint. This effect was dose dependent. It was prevented by coadministration of etanercept or by an inhibitor of p38, and it was attenuated by systemic application of a COX inhibitor. Patch clamp recordings from isolated DRG neurons showed a rapid increase in neuronal excitability induced by TNF.Conclusion. TNF can induce a long-lasting sensitization of joint nociceptors to mechanical stimuli and thus can induce long-lasting mechanical hyperalgesia in joints. TNF can act directly on neurons, underscoring its role as a sensitizing pain mediator.

Increased inflammatory cytokine expression in the vastus lateralis of patients with knee osteoarthritis

“…Inflammation of the synovial joint is an inseparable part of knee OA and leads to pain and disability (2). The increased inflammation and pain associated with OA may reduce the use of the knee extensor muscles in order to lessen the joint load associated with knee function (3).…”

Peripheral Neurokinin-1 Receptors Contribute to Kaolin-Induced Acute Monoarthritis in Rats

“…Once in the joint, they produce reactive oxygen species and cytokines, thus contributing to an ongoing state of inflammation in the joint and joint destruction [29,30,31,32]. Cytokines can also be released both by resident and infiltrating cells, including fibroblast-like synoviocytes [33,34]. The cytokines not only promote and maintain inflammation, but they are also directly related to the generation and maintenance of pain by sensitising sensory neurons innervating the joint [35,36].…”

Methotrexate chemotherapy triggers touch-evoked pain and increased CGRP-positive sensory fibres in the tibial periosteum of young rats

“…Interestingly, intrathecal gene therapy with anti-inflammatory cytokine IL-10 inhibited Paclitaxel chemotherapy-induced mechanical allodynia and expression of pro-inflammatory cytokines TNF-α and IL-1 [35]. In addition, in a rat model of antigen-induced arthritis, TNF-α and IL-6 were found contributors of nociception and hyperalgesia (increased pain induced by a noxious stimulator) as a result of mechanical stimulation [36,37]. Since up-regulation of proinflammatory cytokines TNF-α and IL-6 proteins in circulation after MTX treatment (shown in our recent study) [10] coincides with the increase in mechanical allodynia found in the current study, this suggests inflammation induced by MTX treatment could perhaps contribute to the decrease in pain threshold to non-noxious stimulation.…”