Abstract
Proinflammatory cytokines are major mediators in the pathogenesis of diseases of joints such as rheumatoid arthritis and osteoarthritis. This review emphasizes that proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6 and interleukin-17 are also mediators of pain by directly acting on the nociceptive system. Proportions of nociceptive sensory neurons express receptors for these cytokines, and the application of cytokines rapidly changes the excitability, ion currents and second messenger systems of these neurons. By inducing persistent sensitization of nociceptive sensory neurons (C- and a proportion of Aδ-fibers) for mechanical stimuli in the joint (a process called peripheral sensitization), these cytokines significantly contribute to the persistent hyperalgesia typical for many disease states of the joint. In addition, the disease-associated release of cytokines in the spinal cord supports the generation of central sensitization. The therapeutic neutralization of proinflammatory cytokines thus not only reduces the process of inflammation but may directly reduce hyperalgesia and pain by reversing the neuronal effects of cytokines. It is emerging that different cytokines have different actions on neurons. The neutralization of tumor necrosis factor-alpha reduces both mechanical and thermal hyperalgesia of the joint. The neutralization of interleukin-1beta attenuates thermal hyperalgesia whereas the neutralization of interleukin-6 and interleukin-17 mainly reduces mechanical hyperalgesia. These different effects are partly explained by influencing different target molecules in sensory neurons. For example, in cultured sensory neurons tumor necrosis factor-alpha and interleukin-1beta upregulate the TRPV1 ion channel, which is involved in the transduction of heat stimuli, consistent with an effect of these cytokines in thermal hyperalgesia. By contrast, interleukin-17 upregulates the TRPV4 ion channel, which has a role in the transduction of mechanical stimuli. Thus, the analgesic potential of neutralizing cytokines seems to depend on which cytokine is mainly involved in the particular pain state.
Highlights
Cytokines are major inflammatory mediators which induce and maintain disease processes such as arthritis
Spinal application of either etanercept or an antibody to TNFR1 during the development of joint inflammation significantly attenuated the generation of inflammation-evoked spinal hyperexcitability, which is characterized by widespread pain sensitization beyond the inflamed joint. These findings indicate that the production and release of tumor necrosis factor (TNF)-α in the spinal cord supports the generation of inflammationevoked spinal hypersensitivity [23]
Through comparison of the effects of different cytokines on sensory neurons the concept begins to emerge that different cytokines are involved in particular qualities of pain, such as mechanical or thermal hyperalgesia (Figure 5)
Summary
Cytokines are major inflammatory mediators which induce and maintain disease processes such as arthritis. During development of inflammation in the joint, nociceptive spinal cord neurons develop a state of hyperexcitability (called central sensitization) which increases the gain of the nociceptive processing [9] In this context it is important that TNF-α is produced in the inflamed tissue and in the spinal cord, namely by glial cells [11]. By contrast, repeated intraperitoneal injection of sgp130 in the course of AIA reduced mechanical hyperalgesia only weakly, at a time point where AIA is already in the process of remission (Figure 3) [31] This behavioral pattern of IL-6 neutralization corresponds to the neuronal effects of IL-6, indicating that endogenous IL-6 plays a significant role in the generation of arthritic joint pain but that the IL-6-induced hyperexcitability is difficult to reverse once it is established. Since IL-17RA is expressed in satellite cells of DRGs, IL-17A may be involved in neuropathic pain because satellite cells play a role in the pathological destructive and repair processes in DRGs in the aftermath of neuronal damage [56]
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