Nociceptive neurons detect cytokines in arthritis

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-1 beta, 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-1 beta 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-1 beta 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.

Figure 1

General diagram of how proinflammatory cytokines contribute to the generation of pain. The indirect way is induced by mediators such as prostaglandins that are produced during inflammation. The direct way indicates direct effects of cytokines on sensory neurons.

Figure 2

General overview of effects of peripheral and spinal cytokines on joint nociceptors, the spinal cord, and the brain. Note that each cytokine has its own profile of actions (see text for details). DRG, dorsal root ganglia; TRP, transient receptor potential.

Figure 3

Effects of proinflammatory cytokines on the responsiveness of nociceptive sensory neurons (Aδ- and C-fibers) of the joint to mechanical stimulation of the joint upon intra-articular injection of different cytokines into the normal knee joint, and long-term effects of the neutralization of these cytokines on pain behavior in the model of antigen-induced arthritis (AIA).

Figure 4

Model showing how cytokines sensitize nociceptive sensory neurons to stimulation. The diagram displays the model of a sensory ending of a nociceptive sensory neuron in the joint. The membrane of the neuron expresses ion channels for the transduction of stimuli (their opening by stimuli causes depolarizing sensor potentials in the ending) and voltage-gated ion channels for the regulation of the membrane potential, the excitability and the generation of the action potentials. In addition, the ending expresses receptors for cytokines which activate intracellular pathways. The latter can change the response properties of the ion channels and/or their expression in the membrane. Membrane receptors for other mediators (for example, prostaglandins) are not displayed. TRP, transient receptor potential.

Figure 5

Profile of different cytokines in the generation of hyperalgesia. IL-17, IL-6, and TNF-α cause mechanical hyperalgesia, whereas thermal hyperalgesia is mainly induced by TNF-α and IL-1β.